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Zhang D, Xie D, Qu Y, Mu D, Wang S. Digging deeper into necrotizing enterocolitis: bridging clinical, microbial, and molecular perspectives. Gut Microbes 2025; 17:2451071. [PMID: 39826099 DOI: 10.1080/19490976.2025.2451071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 12/26/2024] [Accepted: 01/02/2025] [Indexed: 01/20/2025] Open
Abstract
Necrotizing Enterocolitis (NEC) is a severe, life-threatening inflammatory condition of the gastrointestinal tract, especially affecting preterm infants. This review consolidates evidence from various biomedical disciplines to elucidate the complex pathogenesis of NEC, integrating insights from clinical, microbial, and molecular perspectives. It emphasizes the modulation of NEC-associated inflammatory pathways by probiotics and novel biologics, highlighting their therapeutic potential. We further critically examine dysbiotic alterations within the gut microbiota, with a particular focus on imbalances in bacterial and viral communities, which may contribute to the onset of NEC. The intricate interactions among toll-like receptor 4 (TLR4), microvascular integrity, immune activation, and the inflammatory milieu are meticulously summarized, offering a sophisticated understanding of NEC pathophysiology. This academic review aims to enhance the etiological comprehension of NEC, promote the development of targeted therapeutic interventions, and impart the significant impact of perinatal factors on the formulation of preventive and curative strategies for the disease.
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Affiliation(s)
- Deshuang Zhang
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China
- Division of Neonatology/Pediatric Surgery, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Dongke Xie
- Division of Neonatology/Pediatric Surgery, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yi Qu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China
| | - Dezhi Mu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China
| | - Shaopu Wang
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China
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2
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Jimenez-Sanchez M, Celiberto LS, Yang H, Sham HP, Vallance BA. The gut-skin axis: a bi-directional, microbiota-driven relationship with therapeutic potential. Gut Microbes 2025; 17:2473524. [PMID: 40050613 PMCID: PMC11901370 DOI: 10.1080/19490976.2025.2473524] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/20/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
This review explores the emerging term "gut-skin axis" (GSA), describing the bidirectional signaling that occurs between the skin and the gastrointestinal tract under both homeostatic and disease conditions. Central to GSA communication are the gut and skin microbiota, the microbial communities that colonize these barrier surfaces. By influencing diverse host pathways, including innate immune, vitamin D receptor, and Aryl hydrocarbon receptor signaling, a balanced microbiota contributes to both tissue homeostasis and host defense. In contrast, microbiota imbalance, or dysbiosis at one site, can lead to local barrier dysfunction, resulting in the activation of signaling pathways that can disrupt tissue homeostasis at the other site, potentially leading to inflammatory skin conditions such as atopic dermatitis and psoriasis, or gut diseases like Inflammatory Bowel Disease. To date, most research on the GSA has examined the impact of the gut microbiota and diet on skin health, but recent studies show that exposing the skin to ultraviolet B-light can beneficially modulate both the gut microbiome and intestinal health. Thus, despite the traditional focus of clinicians and researchers on these organ systems as distinct, the GSA offers new opportunities to better understand the pathogenesis of cutaneous and gastrointestinal diseases and promote health at both sites.
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Affiliation(s)
- Maira Jimenez-Sanchez
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada
| | - Larissa S. Celiberto
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada
| | - Hyungjun Yang
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada
| | - Ho Pan Sham
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada
| | - Bruce A. Vallance
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada
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3
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Soranno DE, Coopersmith CM, Brinkworth JF, Factora FNF, Muntean JH, Mythen MG, Raphael J, Shaw AD, Vachharajani V, Messer JS. A review of gut failure as a cause and consequence of critical illness. Crit Care 2025; 29:91. [PMID: 40011975 PMCID: PMC11866815 DOI: 10.1186/s13054-025-05309-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 02/05/2025] [Indexed: 02/28/2025] Open
Abstract
In critical illness, all elements of gut function are perturbed. Dysbiosis develops as the gut microbial community loses taxonomic diversity and new virulence factors appear. Intestinal permeability increases, allowing for translocation of bacteria and/or bacterial products. Epithelial function is altered at a cellular level and homeostasis of the epithelial monolayer is compromised by increased intestinal epithelial cell death and decreased proliferation. Gut immunity is impaired with simultaneous activation of maladaptive pro- and anti-inflammatory signals leading to both tissue damage and susceptibility to infections. Additionally, splanchnic vasoconstriction leads to decreased blood flow with local ischemic changes. Together, these interrelated elements of gastrointestinal dysfunction drive and then perpetuate multi-organ dysfunction syndrome. Despite the clear importance of maintaining gut homeostasis, there are very few reliable measures of gut function in critical illness. Further, while multiple therapeutic strategies have been proposed, most have not been shown to conclusively demonstrate benefit, and care is still largely supportive. The key role of the gut in critical illness was the subject of the tenth Perioperative Quality Initiative meeting, a conference to summarize the current state of the literature and identify key knowledge gaps for future study. This review is the product of that conference.
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Affiliation(s)
- Danielle E Soranno
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Craig M Coopersmith
- Department of Surgery and Emory Critical Care Center, Emory University, Atlanta, GA, USA
| | - Jessica F Brinkworth
- Department of Anthropology, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Faith N F Factora
- Intensive Care and Resuscitation, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
| | - Julia H Muntean
- Intensive Care and Resuscitation, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
| | - Monty G Mythen
- Perioperative Medicine, University College London, London, England
| | - Jacob Raphael
- Anesthesiology and Perioperative Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Andrew D Shaw
- Intensive Care and Resuscitation, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
| | - Vidula Vachharajani
- Department of Pulmonary and Critical Care, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
| | - Jeannette S Messer
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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4
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Cavaillon JM, Chaudry IH. Facing stress and inflammation: From the cell to the planet. World J Exp Med 2024; 14:96422. [PMID: 39713080 PMCID: PMC11551703 DOI: 10.5493/wjem.v14.i4.96422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/27/2024] [Accepted: 09/19/2024] [Indexed: 10/31/2024] Open
Abstract
As identified in 1936 by Hans Selye, stress is shaping diseases through the induction of inflammation. But inflammation display some yin yang properties. On one hand inflammation is merging with the innate immune response aimed to fight infectious or sterile insults, on the other hand inflammation favors chronic physical or psychological disorders. Nature has equipped the cells, the organs, and the individuals with mediators and mechanisms that allow them to deal with stress, and even a good stress (eustress) has been associated with homeostasis. Likewise, societies and the planet are exposed to stressful settings, but wars and global warming suggest that the regulatory mechanisms are poorly efficient. In this review we list some inducers of the physiological stress, psychologic stress, societal stress, and planetary stress, and mention some of the great number of parameters which affect and modulate the response to stress and render it different from an individual to another, from the cellular level to the societal one. The cell, the organ, the individual, the society, and the planet share many stressors of which the consequences are extremely interconnected ending in the domino effect and the butterfly effect.
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Affiliation(s)
| | - Irshad H Chaudry
- Department of Surgery, University of Alabama Birmingham, Birmingham, AL 35294, United States
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5
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Barreto-Duran E, Synowiec A, Szczepański A, Gałuszka-Bulaga A, Węglarczyk K, Baj-Krzyworzeka M, Siedlar M, Bochenek M, Dufva M, Dogan AA, Lenart M, Pyrc K. Development of an intestinal mucosa ex vivo co-culture model to study viral infections. J Virol 2024; 98:e0098724. [PMID: 39212448 PMCID: PMC11495016 DOI: 10.1128/jvi.00987-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 07/17/2024] [Indexed: 09/04/2024] Open
Abstract
Studying viral infections necessitates well-designed cell culture models to deepen our understanding of diseases and develop effective treatments. In this study, we present a readily available ex vivo 3D co-culture model replicating the human intestinal mucosa. The model combines fully differentiated human intestinal epithelium (HIE) with human monocyte-derived macrophages (hMDMs) and faithfully mirrors the in vivo structural and organizational properties of intestinal mucosal tissues. Specifically, it mimics the lamina propria, basement membrane, and the air-exposed epithelial layer, enabling the pioneering observation of macrophage migration through the tissue to the site of viral infection. In this study, we applied the HIE-hMDMs model for the first time in viral infection studies, infecting the model with two globally significant viruses: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human norovirus GII.4. The results demonstrate the model's capability to support the replication of both viruses and show the antiviral role of macrophages, determined by their migration to the infection site and subsequent direct contact with infected epithelial cells. In addition, we evaluated the production of cytokines and chemokines in the intestinal niche, observing an increased interleukin-8 production during infection. A parallel comparison using a classical in vitro cell line model comprising Caco-2 and THP-1 cells for SARS-CoV-2 experiments confirmed the utility of the HIE-hMDMs model in viral infection studies. Our data show that the ex vivo tissue models hold important implications for advances in virology research.IMPORTANCEThe fabrication of intricate ex vivo tissue models holds important implications for advances in virology research. The co-culture model presented here provides distinct spatial and functional attributes not found in simplified models, enabling the evaluation of macrophage dynamics under severe acute respiratory syndrome coronavirus 2 and human norovirus (HuNoV) infections in the intestine. Moreover, these models, comprised solely of primary cells, facilitate the study of difficult-to-replicate viruses such as HuNoV, which cannot be studied in cell line models, and offer the opportunity for personalized treatment evaluations using patient cells. Similar co-cultures have been established for the study of bacterial infections and different characteristics of the intestinal tissue. However, to the best of our knowledge, a similar intestinal model for the study of viral infections has not been published before.
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Affiliation(s)
- Emilia Barreto-Duran
- Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Aleksandra Synowiec
- Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Kraków, Poland
| | - Artur Szczepański
- Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Adrianna Gałuszka-Bulaga
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Kazimierz Węglarczyk
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Monika Baj-Krzyworzeka
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Maciej Siedlar
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Michał Bochenek
- Flow Cytometry Facility, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Martin Dufva
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Asli Aybike Dogan
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Marzena Lenart
- Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Krzysztof Pyrc
- Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
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6
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Guo Y, Ren C, He Y, Wu Y, Yang X. Deciphering the spatiotemporal transcriptional landscape of intestinal diseases (Review). Mol Med Rep 2024; 30:157. [PMID: 38994768 PMCID: PMC11258600 DOI: 10.3892/mmr.2024.13281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 04/19/2024] [Indexed: 07/13/2024] Open
Abstract
The intestines are the largest barrier organ in the human body. The intestinal barrier plays a crucial role in maintaining the balance of the intestinal environment and protecting the intestines from harmful bacterial invasion. Single‑cell RNA sequencing technology allows the detection of the different cell types in the intestine in two dimensions and the exploration of cell types that have not been fully characterized. The intestinal mucosa is highly complex in structure, and its proper functioning is linked to multiple structures in the proximal‑distal intestinal and luminal‑mucosal axes. Spatial localization is at the core of the efforts to explore the interactions between the complex structures. Spatial transcriptomics (ST) is a method that allows for comprehensive tissue analysis and the acquisition of spatially separated genetic information from individual cells, while preserving their spatial location and interactions. This approach also prevents the loss of fragile cells during tissue disaggregation. The emergence of ST technology allows us to spatially dissect enzymatic processes and interactions between multiple cells, genes, proteins and signals in the intestine. This includes the exchange of oxygen and nutrients in the intestine, different gradients of microbial populations and the role of extracellular matrix proteins. This regionally precise approach to tissue studies is gaining more acceptance and is increasingly applied in the investigation of disease mechanisms related to the gastrointestinal tract. Therefore, this review summarized the application of ST in gastrointestinal diseases.
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Affiliation(s)
- Yajing Guo
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, P.R. China
| | - Chao Ren
- Graduate School, Hunan University of Traditional Chinese Medicine, Changsha, Hunan 410208, P.R. China
| | - Yuxi He
- Department of Digestive Medicine, Chongqing City Hospital of Traditional Chinese Medicine, Chongqing 400021, P.R. China
| | - Yue Wu
- Department of Digestive Medicine, Chongqing City Hospital of Traditional Chinese Medicine, Chongqing 400021, P.R. China
| | - Xiaojun Yang
- Department of Digestive Medicine, Chongqing City Hospital of Traditional Chinese Medicine, Chongqing 400021, P.R. China
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7
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Cavaillon JM, Chousterman BG, Skirecki T. Compartmentalization of the inflammatory response during bacterial sepsis and severe COVID-19. JOURNAL OF INTENSIVE MEDICINE 2024; 4:326-340. [PMID: 39035623 PMCID: PMC11258514 DOI: 10.1016/j.jointm.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 01/04/2024] [Accepted: 01/06/2024] [Indexed: 07/23/2024]
Abstract
Acute infections cause local and systemic disorders which can lead in the most severe forms to multi-organ failure and eventually to death. The host response to infection encompasses a large spectrum of reactions with a concomitant activation of the so-called inflammatory response aimed at fighting the infectious agent and removing damaged tissues or cells, and the anti-inflammatory response aimed at controlling inflammation and initiating the healing process. Fine-tuning at the local and systemic levels is key to preventing local and remote injury due to immune system activation. Thus, during bacterial sepsis and Coronavirus disease 2019 (COVID-19), concomitant systemic and compartmentalized pro-inflammatory and compensatory anti-inflammatory responses are occurring. Immune cells (e.g., macrophages, neutrophils, natural killer cells, and T-lymphocytes), as well as endothelial cells, differ from one compartment to another and contribute to specific organ responses to sterile and microbial insult. Furthermore, tissue-specific microbiota influences the local and systemic response. A better understanding of the tissue-specific immune status, the organ immunity crosstalk, and the role of specific mediators during sepsis and COVID-19 can foster the development of more accurate biomarkers for better diagnosis and prognosis and help to define appropriate host-targeted treatments and vaccines in the context of precision medicine.
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Affiliation(s)
| | - Benjamin G. Chousterman
- Department of Anesthesia and Critical Care, Lariboisière University Hospital, DMU Parabol, APHP Nord, Paris, France
- Inserm U942, University of Paris, Paris, France
| | - Tomasz Skirecki
- Department of Translational Immunology and Experimental Intensive Care, Centre of Postgraduate Medical Education, Warsaw, Poland
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8
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Lu X, Shi Z, Jiang L, Zhang S. Maternal gut microbiota in the health of mothers and offspring: from the perspective of immunology. Front Immunol 2024; 15:1362784. [PMID: 38545107 PMCID: PMC10965710 DOI: 10.3389/fimmu.2024.1362784] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 02/28/2024] [Indexed: 04/17/2024] Open
Abstract
Due to the physiological alteration during pregnancy, maternal gut microbiota changes following the metabolic processes. Recent studies have revealed that maternal gut microbiota is closely associated with the immune microenvironment in utero during pregnancy and plays a vital role in specific pregnancy complications, including preeclampsia, gestational diabetes, preterm birth and recurrent miscarriages. Some other evidence has also shown that aberrant maternal gut microbiota increases the risk of various diseases in the offspring, such as allergic and neurodevelopmental disorders, through the immune alignment between mother and fetus and the possible intrauterine microbiota. Probiotics and the high-fiber diet are effective inventions to prevent mothers and fetuses from diseases. In this review, we summarize the role of maternal gut microbiota in the development of pregnancy complications and the health condition of future generations from the perspective of immunology, which may provide new therapeutic strategies for the health management of mothers and offspring.
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Affiliation(s)
- Xiaowen Lu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction, Management of Zhejiang Province, Hangzhou, China
| | - Zhan Shi
- Department of Obstetrics and Gynecology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China
| | - Lingling Jiang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction, Management of Zhejiang Province, Hangzhou, China
| | - Songying Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction, Management of Zhejiang Province, Hangzhou, China
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Giovanetti M, Pannella G, Altomare A, Rocchi G, Guarino M, Ciccozzi M, Riva E, Gherardi G. Exploring the Interplay between COVID-19 and Gut Health: The Potential Role of Prebiotics and Probiotics in Immune Support. Viruses 2024; 16:370. [PMID: 38543736 PMCID: PMC10975078 DOI: 10.3390/v16030370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/23/2024] [Accepted: 02/26/2024] [Indexed: 05/23/2024] Open
Abstract
The COVID-19 pandemic has profoundly impacted global health, leading to extensive research focused on developing strategies to enhance outbreak response and mitigate the disease's severity. In the aftermath of the pandemic, attention has shifted towards understanding and addressing long-term health implications, particularly in individuals experiencing persistent symptoms, known as long COVID. Research into potential interventions to alleviate long COVID symptoms has intensified, with a focus on strategies to support immune function and mitigate inflammation. One area of interest is the gut microbiota, which plays a crucial role in regulating immune responses and maintaining overall health. Prebiotics and probiotics, known for their ability to modulate the gut microbiota, have emerged as potential therapeutic agents in bolstering immune function and reducing inflammation. This review delves into the intricate relationship between long COVID, the gut microbiota, and immune function, with a specific focus on the role of prebiotics and probiotics. We examine the immune response to long COVID, emphasizing the importance of inflammation and immune regulation in the persistence of symptoms. The potential of probiotics in modulating immune responses, including their mechanisms in combating viral infections such as COVID-19, is discussed in detail. Clinical evidence supporting the use of probiotics in managing long COVID symptoms is summarized, highlighting their role as adjunctive therapy in addressing various aspects of SARS-CoV-2 infection and its aftermath.
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Affiliation(s)
- Marta Giovanetti
- Sciences and Technologies for Sustainable Development and One Health, Università Campus Bio-Medico di Roma, 00128 Roma, Italy; (G.P.); (A.A.)
- Climate Amplified Diseases and Epidemics (CLIMADE), Brasilia 70070-130, Brazil
- Instituto Rene Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-002, Brazil
| | - Gianfranco Pannella
- Sciences and Technologies for Sustainable Development and One Health, Università Campus Bio-Medico di Roma, 00128 Roma, Italy; (G.P.); (A.A.)
- Department of Agricultural, Enviromental and Food Science, University of Molise, 86100 Campobasso, Italy
| | - Annamaria Altomare
- Sciences and Technologies for Sustainable Development and One Health, Università Campus Bio-Medico di Roma, 00128 Roma, Italy; (G.P.); (A.A.)
- Research Unit of Gastroenterology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (G.R.); (M.G.)
| | - Giulia Rocchi
- Research Unit of Gastroenterology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (G.R.); (M.G.)
| | - Michele Guarino
- Research Unit of Gastroenterology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (G.R.); (M.G.)
- Operative Research Unit of Gastroenterology, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | - Massimo Ciccozzi
- Unit of Medical Statistics and Molecular Epidemiology, University Campus Bio-Medico of Rome, 00128 Roma, Italy;
| | - Elisabetta Riva
- Unit of Virology, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy;
- Applied Bacteriological Sciences Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Giovanni Gherardi
- Applied Bacteriological Sciences Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
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10
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Sakellariou S, Perdiki M, Bamias G, Delladetsima I. Colonic mucosa barrier defects in collagenous and ischemic colitis. Histol Histopathol 2024; 39:41-47. [PMID: 37161950 DOI: 10.14670/hh-18-623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
AIMS The subepithelial myofibroblasts (SEMFs) and the subepithelial band of macrophages (SEBM) are major components of the colonic mucosa barrier. Although their role in homeostasis is widely recognized, their contribution to disease states is largely unknown. Our aim was to explore histological characteristics of SEMFs and SEBM in collagenous and ischemic colitis in order to identify specific changes in distinct mucosa backgrounds lacking significant inflammation. METHODS SEMFs, SEBM and lamina propria (LP) macrophages were identified immunohistochemically by alpha smooth muscle Actin and Cluster of Differentiation 68 respectively in 38 colonic biopsies [14 collagenous colitis (CC), 14 ischemic colitis (IC), 10 normal mucosa]. RESULTS In CC, SEMFs were rarely detectable in the collagenous band while aSMA-negative pericryptal fibroblast-like cells appeared. In lower LP interconnecting SEMFs processes were formed. SEBM was preserved in areas with a collagenous layer up to 20 μm. In thicker layers, it was fragmented and gradually disappeared in parallel with engulfment of enlarged macrophages. LP macrophages were usually increased. In IC, slight SEMFs changes preceded discernible epithelial alterations. Rounding, disintegration and extinction of SEMFs constituted successive alterations coinciding with crypt shrinkage and denudation. SEBM displayed total or almost total abolishment in areas with crypt damage but also in sites with minimal changes and in adjacent normal mucosa. CONCLUSION Our findings provide evidence of impairment of both mucosa barrier constituents in CC and IC. In CC, histological alterations are closely related to the collagenous layer which seems to affect SEMFs differentiation and migration as well as SEBM integrity. The early extinction of SEBM in IC is indicative of its high sensitivity to hypoxia and hypoperfusion.
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Affiliation(s)
- Stratigoula Sakellariou
- 1st Department of Pathology, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
| | - Marina Perdiki
- Department of Pathology, Linköping University, Linköping, Sweden
| | - Giorgos Bamias
- GI Unit, 3rd Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria General Hospital, Athens, Greece
| | - Ioanna Delladetsima
- 1st Department of Pathology, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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11
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Zhang H, Wang X, Zhang J, He Y, Yang X, Nie Y, Sun L. Crosstalk between gut microbiota and gut resident macrophages in inflammatory bowel disease. J Transl Int Med 2023; 11:382-392. [PMID: 38130639 PMCID: PMC10732497 DOI: 10.2478/jtim-2023-0123] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023] Open
Abstract
Macrophages residing in the gut maintain gut homeostasis by orchestrating patho-gens and innocuous antigens. A disturbance in macrophages leads to gut inflamma-tion, causing conditions such as inflammatory bowel disease (IBD). Macrophages ex-hibit remarkable plasticity, as they are sensitive to various signals in the tissue micro-environment. During the recent decades, gut microbiota has been highlighted refer-ring to their critical roles in immunity response. Microbiome-derived metabolites and products can interact with macrophages to participate in the progression of IBD. In this review, we describe recent findings in this field and provide an overview of the current understanding of microbiota-macrophages interactions in IBD, which may lead to the development of new targets and treatment options for patients with IBD.
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Affiliation(s)
- Haohao Zhang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. School of Medicine, Northwest University, Xi'an, Shaaxi Province, China
- State Key Laboratory of Targeting Oncology, National Center for International Re-search of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Xueying Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. School of Medicine, Northwest University, Xi'an, Shaaxi Province, China
| | - Jing Zhang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. School of Medicine, Northwest University, Xi'an, Shaaxi Province, China
| | - Yixuan He
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. School of Medicine, Northwest University, Xi'an, Shaaxi Province, China
| | - Xiumin Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. School of Medicine, Northwest University, Xi'an, Shaaxi Province, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, Shaaxi Province, China
| | - Lijuan Sun
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. School of Medicine, Northwest University, Xi'an, Shaaxi Province, China
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, Shaaxi Province, China
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12
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Wei J, Meng Z, Li Z, Dang D, Wu H. New insights into intestinal macrophages in necrotizing enterocolitis: the multi-functional role and promising therapeutic application. Front Immunol 2023; 14:1261010. [PMID: 37841247 PMCID: PMC10568316 DOI: 10.3389/fimmu.2023.1261010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 09/13/2023] [Indexed: 10/17/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is an inflammatory intestinal disease that profoundly affects preterm infants. Currently, the pathogenesis of NEC remains controversial, resulting in limited treatment strategies. The preterm infants are thought to be susceptible to gut inflammatory disorders because of their immature immune system. In early life, intestinal macrophages (IMφs), crucial components of innate immunity, demonstrate functional plasticity and diversity in intestinal development, resistance to pathogens, maintenance of the intestinal barrier, and regulation of gut microbiota. When the stimulations of environmental, dietary, and bacterial factors interrupt the homeostatic processes of IMφs, they will lead to intestinal disease, such as NEC. This review focuses on the IMφs related pathogenesis in NEC, discusses the multi-functional roles and relevant molecular mechanisms of IMφs in preterm infants, and explores promising therapeutic application for NEC.
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Affiliation(s)
- Jiaqi Wei
- Department of Neonatology, First Hospital of Jilin University, Changchun, China
| | - Zhaoli Meng
- Department of Translational Medicine Research Institute, First Hospital of Jilin University, Changchun, China
| | - Zhenyu Li
- Department of Neonatology, First Hospital of Jilin University, Changchun, China
| | - Dan Dang
- Department of Neonatology, First Hospital of Jilin University, Changchun, China
| | - Hui Wu
- Department of Neonatology, First Hospital of Jilin University, Changchun, China
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13
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Zhao L, Xiao J, Li S, Guo Y, Fu R, Hua S, Du Y, Xu S. The interaction between intestinal microenvironment and stroke. CNS Neurosci Ther 2023; 29 Suppl 1:185-199. [PMID: 37309254 PMCID: PMC10314114 DOI: 10.1111/cns.14275] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 05/09/2023] [Accepted: 05/10/2023] [Indexed: 06/14/2023] Open
Abstract
BACKGROUND Stroke is not only a major cause of disability but also the third leading cause of death, following heart disease and cancer. It has been established that stroke causes permanent disability in 80% of survivors. However, current treatment options for this patient population are limited. Inflammation and immune response are major features that are well-recognized to occur after a stroke. The gastrointestinal tract hosts complex microbial communities, the largest pool of immune cells, and forms a bidirectional regulation brain-gut axis with the brain. Recent experimental and clinical studies have highlighted the importance of the relationship between the intestinal microenvironment and stroke. Over the years, the influence of the intestine on stroke has emerged as an important and dynamic research direction in biology and medicine. AIMS In this review, we describe the structure and function of the intestinal microenvironment and highlight its cross-talk relationship with stroke. In addition, we discuss potential strategies aiming to target the intestinal microenvironment during stroke treatment. CONCLUSION The structure and function of the intestinal environment can influence neurological function and cerebral ischemic outcome. Improving the intestinal microenvironment by targeting the gut microbiota may be a new direction in treating stroke.
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Affiliation(s)
- Linna Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- National Clinical Research Center for Chinese Medicine Acupuncture and MoxibustionFirst Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- Tianjin Key Laboratory of Translational Research of TCM Prescription and SyndromeTianjinChina
| | - Jie Xiao
- First Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- National Clinical Research Center for Chinese Medicine Acupuncture and MoxibustionFirst Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- Tianjin University of Traditional Chinese MedicineTianjinChina
| | - Songlin Li
- First Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- National Clinical Research Center for Chinese Medicine Acupuncture and MoxibustionFirst Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- Tianjin University of Traditional Chinese MedicineTianjinChina
| | - Yuying Guo
- First Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- National Clinical Research Center for Chinese Medicine Acupuncture and MoxibustionFirst Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- Tianjin Key Laboratory of Translational Research of TCM Prescription and SyndromeTianjinChina
| | - Rong Fu
- First Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- National Clinical Research Center for Chinese Medicine Acupuncture and MoxibustionFirst Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- Tianjin University of Traditional Chinese MedicineTianjinChina
| | - Shengyu Hua
- Tianjin University of Traditional Chinese MedicineTianjinChina
| | - Yuzheng Du
- First Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- National Clinical Research Center for Chinese Medicine Acupuncture and MoxibustionFirst Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
| | - Shixin Xu
- First Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- National Clinical Research Center for Chinese Medicine Acupuncture and MoxibustionFirst Teaching Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
- Tianjin Key Laboratory of Translational Research of TCM Prescription and SyndromeTianjinChina
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14
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Ogino T, Takeda K. Immunoregulation by antigen-presenting cells in human intestinal lamina propria. Front Immunol 2023; 14:1138971. [PMID: 36845090 PMCID: PMC9947491 DOI: 10.3389/fimmu.2023.1138971] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023] Open
Abstract
Antigen-presenting cells, including macrophages and dendritic cells, are a type of innate immune cells that can induce the differentiation of T cells and activate the adaptive immune response. In recent years, diverse subsets of macrophages and dendritic cells have been identified in the intestinal lamina propria of mice and humans. These subsets contribute to the maintenance of intestinal tissue homeostasis by regulating the adaptive immune system and epithelial barrier function through interaction with intestinal bacteria. Further investigation of the roles of antigen-presenting cells localized in the intestinal tract may lead to the elucidation of inflammatory bowel disease pathology and the development of novel treatment approaches.
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Affiliation(s)
- Takayuki Ogino
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
- Department of Therapeutics for Inflammatory Bowel Diseases, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Kiyoshi Takeda
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Japan
- Immunology Frontier Research Center, Osaka University, Suita, Japan
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15
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Sertznig H, Roesmann F, Wilhelm A, Heininger D, Bleekmann B, Elsner C, Santiago M, Schuhenn J, Karakoese Z, Benatzy Y, Snodgrass R, Esser S, Sutter K, Dittmer U, Widera M. SRSF1 acts as an IFN-I-regulated cellular dependency factor decisively affecting HIV-1 post-integration steps. Front Immunol 2022; 13:935800. [PMID: 36458014 PMCID: PMC9706209 DOI: 10.3389/fimmu.2022.935800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 10/19/2022] [Indexed: 08/24/2023] Open
Abstract
Efficient HIV-1 replication depends on balanced levels of host cell components including cellular splicing factors as the family of serine/arginine-rich splicing factors (SRSF, 1-10). Type I interferons (IFN-I) play a crucial role in the innate immunity against HIV-1 by inducing the expression of IFN-stimulated genes (ISGs) including potent host restriction factors. The less well known IFN-repressed genes (IRepGs) might additionally affect viral replication by downregulating host dependency factors that are essential for the viral life cycle; however, so far, the knowledge about IRepGs involved in HIV-1 infection is very limited. In this work, we could demonstrate that HIV-1 infection and the associated ISG induction correlated with low SRSF1 levels in intestinal lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs) during acute and chronic HIV-1 infection. In HIV-1-susceptible cell lines as well as primary monocyte-derived macrophages (MDMs), expression levels of SRSF1 were transiently repressed upon treatment with specific IFNα subtypes in vitro. Mechanically, 4sU labeling of newly transcribed mRNAs revealed that IFN-mediated SRSF1 repression is regulated on early RNA level. SRSF1 knockdown led to an increase in total viral RNA levels, but the relative proportion of the HIV-1 viral infectivity factor (Vif) coding transcripts, which is essential to counteract APOBEC3G-mediated host restriction, was significantly reduced. In the presence of high APOBEC3G levels, however, increased LTR activity upon SRSF1 knockdown facilitated the overall replication, despite decreased vif mRNA levels. In contrast, SRSF1 overexpression significantly impaired HIV-1 post-integration steps including LTR transcription, alternative splice site usage, and virus particle production. Since balanced SRSF1 levels are crucial for efficient viral replication, our data highlight the so far undescribed role of SRSF1 acting as an IFN-modulated cellular dependency factor decisively regulating HIV-1 post-integration steps.
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Affiliation(s)
- Helene Sertznig
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Fabian Roesmann
- Institute for Medical Virology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
| | - Alexander Wilhelm
- Institute for Medical Virology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
| | - Delia Heininger
- Institute for Medical Virology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
| | - Barbara Bleekmann
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Carina Elsner
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Mario Santiago
- Department of Medicine, University of Colorado Denver, Aurora, CO, United States
| | - Jonas Schuhenn
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Zehra Karakoese
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Yvonne Benatzy
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt am Main, Frankfurt, Germany
| | - Ryan Snodgrass
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt am Main, Frankfurt, Germany
| | - Stefan Esser
- Clinic of Dermatology, University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Kathrin Sutter
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Marek Widera
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
- Institute for Medical Virology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
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16
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Lacticaseibacillus casei Strain Shirota Modulates Macrophage-Intestinal Epithelial Cell Co-Culture Barrier Integrity, Bacterial Sensing and Inflammatory Cytokines. Microorganisms 2022; 10:microorganisms10102087. [PMID: 36296363 PMCID: PMC9607601 DOI: 10.3390/microorganisms10102087] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/03/2022] [Accepted: 10/06/2022] [Indexed: 11/06/2022] Open
Abstract
Probiotic bacteria modulate macrophage immune inflammatory responses, with functional cytokine responses determined by macrophage subset polarisation, stimulation and probiotic strain. Mucosal macrophages exhibit subset functional heterogeneity but are organised in a 3-dimensional tissue, over-laid by barrier epithelial cells. This study aimed to investigate the effects of the probiotic Lacticaseibacillus casei strain Shirota (LcS) on macrophage-epithelial cell cytokine responses, pattern recognition receptor (PRR) expression and LPS responses and the impacts on barrier integrity. THP-1-derived M1 and M2 subset macrophages were co-cultured in a transwell system with differentiated Caco-2 epithelial cells in the presence or absence of enteropathogenic LPS. Both Caco-2 cells in monoculture and macrophage co-culture were assayed for cytokines, PRR expression and barrier integrity (TEER and ZO-1) by RT-PCR, ELISA, IHC and electrical resistance. Caco-2 monocultures expressed distinct cytokine profiles (IL-6, IL-8, TNFα, endogenous IL-10), PRRs and barrier integrity, determined by inflammatory context (TNFα or IL-1β). In co-culture, LcS rescued ZO-1 and TEER in M2/Caco-2, but not M1/Caco-2. LcS suppressed TLR2, TLR4, MD2 expression in both co-cultures and differentially regulated NOD2, TLR9, Tollip and cytokine secretion. In conclusion, LcS selectively modulates epithelial barrier integrity, pathogen sensing and inflammatory cytokine profile; determined by macrophage subset and activation status.
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17
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Li Y, Wang K, Ding J, Sun S, Ni Z, Yu C. Influence of the gut microbiota on endometriosis: Potential role of chenodeoxycholic acid and its derivatives. Front Pharmacol 2022; 13:954684. [PMID: 36071850 PMCID: PMC9442031 DOI: 10.3389/fphar.2022.954684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/27/2022] [Indexed: 11/28/2022] Open
Abstract
The gut microbiota (GM) has received extensive attention in recent years, and its key role in the establishment and maintenance of health and in the development of diseases has been confirmed. A strong correlation between the GM and the progression of endometriosis (EMS) has been observed in emerging research. Alterations in the composition and function of the GM have been described in many studies on EMS. In contrast, the GM in the environment of EMS, especially the GM metabolites, such as bile acids and short-chain fatty acids that are related to the pathogenesis of EMS, can promote disease progression. Chenodeoxycholic acid (CDCA), as one of the primary bile acids produced in the liver, is metabolized by various enzymes derived from the GM and is critically important in maintaining intestinal homeostasis and regulating lipid and carbohydrate metabolism and innate immunity. Given that the complexity of CDCA as a signalling molecule and the interaction between the GM and EMS have not been clarified, the role of the CDCA and GM in EMS should be understood from a novel perspective. However, few articles on the relationship between CDCA and EMS have been reviewed. Therefore, we review the available and possible potential links between CDCA, the GM and EMS and put forward the hypothesis that CDCA and its derivative obeticholic acid can improve the symptoms of EMS through the GM.
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Affiliation(s)
- Yangshuo Li
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Kaili Wang
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jie Ding
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Shuai Sun
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Zhexin Ni
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China
- *Correspondence: Zhexin Ni, ; Chaoqin Yu,
| | - Chaoqin Yu
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
- *Correspondence: Zhexin Ni, ; Chaoqin Yu,
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18
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Huang Y, Wu M, Xiao H, Liu H, Yang G. Mesalamine-Mediated Amelioration of Experimental Colitis in Piglets Involves Gut Microbiota Modulation and Intestinal Immune Cell Infiltration. Front Immunol 2022; 13:883682. [PMID: 35898495 PMCID: PMC9309220 DOI: 10.3389/fimmu.2022.883682] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 06/17/2022] [Indexed: 11/20/2022] Open
Abstract
Mesalamine (MES), also known as 5-aminosalicylic acid, is effective in treating mild to moderate ulcerative colitis (UC). The mechanisms of its actions are not fully elucidated. The aim of this study was to investigate the effects of MES treatment on intestinal microbiota and immune system in an dextran sulfate sodium (DSS)-induced UC model in postweaning piglets. Eighteen weaned piglets were assigned randomly to the following treatments: control group (CON, distilled water), DSS group (DSS, 3% DSS), and MES group (MES, 3% DSS + 2 g/day MES). Our results showed that MES treatment alleviates DSS-induced colitis in piglets, as evidenced by a reduced diarrhea index score and increased average daily gain (P < 0.05). This is accompanied by decreased diamine oxidase activity, D-lactate level (P < 0.05), and attenuated mucosal damage. MES treatment also decreased the abundance of Methanogens and reduced colon CD11b+ macrophage and CD3+ T-cell infiltrations in piglets with DSS-induced colitis (P < 0.05). Collectively, these data indicate that MES treatment-mediated colitis protection may involve microbiota and immune cell alterations.
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Affiliation(s)
- Yonggang Huang
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Miaomiao Wu
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Hao Xiao
- State Key Laboratory of Livestock and Poultry Breeding, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Hongnan Liu
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Chinese Academy of Sciences, Changsha, China
| | - Guan Yang
- Department of Infectious Diseases and Public Health, City University of Hong Kong, Kowloon, Hong Kong SAR, China
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19
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Tsuruta S, Kawasaki T, Machida M, Iwatsuki K, Inaba A, Shibata S, Shindo T, Nakabayashi K, Hakamada K, Umezawa A, Akutsu H. Development of Human Gut Organoids With Resident Tissue Macrophages as a Model of Intestinal Immune Responses. Cell Mol Gastroenterol Hepatol 2022; 14:726-729.e5. [PMID: 35760286 PMCID: PMC9421619 DOI: 10.1016/j.jcmgh.2022.06.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 12/10/2022]
Affiliation(s)
- Satoru Tsuruta
- Center for Regenerative Medicine, National Center for Child Health and Development, Tokyo, Japan; Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Tomoyuki Kawasaki
- Center for Regenerative Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Masakazu Machida
- Center for Regenerative Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Ken Iwatsuki
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
| | - Akihiko Inaba
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
| | - Shinsuke Shibata
- Electron Microscope Laboratory, Keio University School of Medicine, Tokyo, Japan; Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Tomoko Shindo
- Electron Microscope Laboratory, Keio University School of Medicine, Tokyo, Japan
| | - Kazuhiko Nakabayashi
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Akihiro Umezawa
- Center for Regenerative Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Hidenori Akutsu
- Center for Regenerative Medicine, National Center for Child Health and Development, Tokyo, Japan
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20
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Abraham C, Abreu MT, Turner JR. Pattern Recognition Receptor Signaling and Cytokine Networks in Microbial Defenses and Regulation of Intestinal Barriers: Implications for Inflammatory Bowel Disease. Gastroenterology 2022; 162:1602-1616.e6. [PMID: 35149024 PMCID: PMC9112237 DOI: 10.1053/j.gastro.2021.12.288] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 11/30/2021] [Accepted: 12/10/2021] [Indexed: 12/23/2022]
Abstract
Inflammatory bowel disease is characterized by defects in epithelial function and dysregulated inflammatory signaling by lamina propria mononuclear cells including macrophages and dendritic cells in response to microbiota. In this review, we focus on the role of pattern recognition receptors in the inflammatory response as well as epithelial barrier regulation. We explore cytokine networks that increase inflammation, regulate paracellular permeability, cause epithelial damage, up-regulate epithelial proliferation, and trigger restitutive processes. We focus on studies using patient samples as well as speculate on pathways that can be targeted to more holistically treat patients with inflammatory bowel disease.
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Affiliation(s)
- Clara Abraham
- Department of Internal Medicine, Yale University, New Haven, Connecticut.
| | - Maria T. Abreu
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Miami Leonard Miller School of Medicine, Miami, FL
| | - Jerrold R. Turner
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
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21
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Jasiński M, Biliński J, Basak GW. The Role of the Crosstalk Between Gut Microbiota and Immune Cells in the Pathogenesis and Treatment of Multiple Myeloma. Front Immunol 2022; 13:853540. [PMID: 35432306 PMCID: PMC9009288 DOI: 10.3389/fimmu.2022.853540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 02/28/2022] [Indexed: 11/26/2022] Open
Abstract
Around 10% of all hematologic malignancies are classified as multiple myeloma (MM), the second most common malignancy within that group. Although massive progress in developing of new drugs against MM has been made in recent years, MM is still an incurable disease, and every patient eventually has relapse refractory to any known treatment. That is why further and non-conventional research elucidating the role of new factors in MM pathogenesis is needed, facilitating discoveries of the new drugs. One of these factors is the gut microbiota, whose role in health and disease is still being explored. This review presents the continuous changes in the gut microbiota composition during our whole life with a particular focus on its impact on our immune system. Additionally, it mainly focuses on the chronic antigenic stimulation of B-cells as the leading mechanism responsible for MM promotion. The sophisticated interactions between microorganisms colonizing our gut, immune cells (dendritic cells, macrophages, neutrophils, T/B cells, plasma cells), and intestinal epithelial cells will be shown. That article summarizes the current knowledge about the initiation of MM cells, emphasizing the role of microorganisms in that process.
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Affiliation(s)
- Marcin Jasiński
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.,Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Jarosław Biliński
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.,Human Biome Institute, Gdańsk, Poland
| | - Grzegorz W Basak
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.,Human Biome Institute, Gdańsk, Poland
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22
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Rohm TV, Keller L, Bosch AJT, AlAsfoor S, Baumann Z, Thomas A, Wiedemann SJ, Steiger L, Dalmas E, Wehner J, Rachid L, Mooser C, Yilmaz B, Fernandez Trigo N, Jauch AJ, Wueest S, Konrad D, Henri S, Niess JH, Hruz P, Ganal-Vonarburg SC, Roux J, Meier DT, Cavelti-Weder C. Targeting colonic macrophages improves glycemic control in high-fat diet-induced obesity. Commun Biol 2022; 5:370. [PMID: 35440795 PMCID: PMC9018739 DOI: 10.1038/s42003-022-03305-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 03/22/2022] [Indexed: 12/13/2022] Open
Abstract
The obesity epidemic continues to worsen worldwide. However, the mechanisms initiating glucose dysregulation in obesity remain poorly understood. We assessed the role that colonic macrophage subpopulations play in glucose homeostasis in mice fed a high-fat diet (HFD). Concurrent with glucose intolerance, pro-inflammatory/monocyte-derived colonic macrophages increased in mice fed a HFD. A link between macrophage numbers and glycemia was established by pharmacological dose-dependent ablation of macrophages. In particular, colon-specific macrophage depletion by intrarectal clodronate liposomes improved glucose tolerance, insulin sensitivity, and insulin secretion capacity. Colonic macrophage activation upon HFD was characterized by an interferon response and a change in mitochondrial metabolism, which converged in mTOR as a common regulator. Colon-specific mTOR inhibition reduced pro-inflammatory macrophages and ameliorated insulin secretion capacity, similar to colon-specific macrophage depletion, but did not affect insulin sensitivity. Thus, pharmacological targeting of colonic macrophages could become a potential therapy in obesity to improve glycemic control. Expansion of pro-inflammatory macrophages in the colon occurs early after high-fat diet initiation, prior to macrophage accumulation in the adipose tissue, in a microbiome-dependent fashion. Macrophage depletion systemically and/or exclusively in the colon improves glucose metabolism.
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Affiliation(s)
- Theresa V Rohm
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Lena Keller
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Angela J T Bosch
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Shefaa AlAsfoor
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Zora Baumann
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | | | - Sophia J Wiedemann
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Laura Steiger
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Elise Dalmas
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Josua Wehner
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Leila Rachid
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Catherine Mooser
- Department of Visceral Surgery und Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Bahtiyar Yilmaz
- Department of Visceral Surgery und Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Nerea Fernandez Trigo
- Department of Visceral Surgery und Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Annaise J Jauch
- Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Stephan Wueest
- Division of Pediatric Endocrinology and Diabetology, and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland
| | - Daniel Konrad
- Division of Pediatric Endocrinology and Diabetology, and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland
| | - Sandrine Henri
- Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, Marseille, France
| | - Jan H Niess
- Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Petr Hruz
- Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Stephanie C Ganal-Vonarburg
- Department of Visceral Surgery und Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Julien Roux
- Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Swiss Institute of Bioinformatics (SIB), Basel, Switzerland
| | - Daniel T Meier
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Claudia Cavelti-Weder
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland. .,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland. .,Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland.
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23
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Vaghari-Tabari M, Targhazeh N, Moein S, Qujeq D, Alemi F, Majidina M, Younesi S, Asemi Z, Yousefi B. From inflammatory bowel disease to colorectal cancer: what's the role of miRNAs? Cancer Cell Int 2022; 22:146. [PMID: 35410210 PMCID: PMC8996392 DOI: 10.1186/s12935-022-02557-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 03/21/2022] [Indexed: 12/27/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease with relapse and remission periods. Ulcerative colitis and Crohn's disease are two major forms of the disease. IBD imposes a lot of sufferings on the patient and has many consequences; however, the most important is the increased risk of colorectal cancer, especially in patients with Ulcerative colitis. This risk is increased with increasing the duration of disease, thus preventing the progression of IBD to cancer is very important. Therefore, it is necessary to know the details of events contributed to the progression of IBD to cancer. In recent years, the importance of miRNAs as small molecules with 20-22 nucleotides has been recognized in pathophysiology of many diseases, in which IBD and colorectal cancer have not been excluded. As a result, the effectiveness of these small molecules as therapeutic target is hopefully confirmed. This paper has reviewed the related studies and findings about the role of miRNAs in the course of events that promote the progression of IBD to colorectal carcinoma, as well as a review about the effectiveness of some of these miRNAs as therapeutic targets.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Forough Alemi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidina
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Simin Younesi
- Schoole of Health and Biomedical Sciences, RMIT University, Melborne, VIC, Australia
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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24
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Hoffner O’Connor M, Berglind A, Kennedy Ng MM, Keith BP, Lynch ZJ, Schaner MR, Steinbach EC, Herzog J, Trad OK, Jeck WR, Arthur JC, Simon JM, Sartor RB, Furey TS, Sheikh SZ. BET Protein Inhibition Regulates Macrophage Chromatin Accessibility and Microbiota-Dependent Colitis. Front Immunol 2022; 13:856966. [PMID: 35401533 PMCID: PMC8988134 DOI: 10.3389/fimmu.2022.856966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/16/2022] [Indexed: 01/14/2023] Open
Abstract
Introduction In colitis, macrophage functionality is altered compared to normal homeostatic conditions. Loss of IL-10 signaling results in an inappropriate chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice. Methods We performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence and absence of lipopolysaccharide (LPS) with and without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization. Results Treatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo resulted in a mild reduction in colitis severity as compared with vehicle-treated mice. Conclusion We identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis.
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Affiliation(s)
- Michelle Hoffner O’Connor
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Ana Berglind
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Meaghan M. Kennedy Ng
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Benjamin P. Keith
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Zachary J. Lynch
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Matthew R. Schaner
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Erin C. Steinbach
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jeremy Herzog
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Omar K. Trad
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - William R. Jeck
- Department of Pathology, Duke University, Durham, NC, United States
| | - Janelle C. Arthur
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jeremy M. Simon
- Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Carolina Institute for Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - R. Balfour Sartor
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Terrence S. Furey
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Shehzad Z. Sheikh
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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25
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Hornsby E, King HW, Peiris M, Buccafusca R, Lee WYJ, Wing ES, Blackshaw LA, Lindsay JO, Stagg AJ. The cation channel TRPM8 influences the differentiation and function of human monocytes. J Leukoc Biol 2022; 112:365-381. [PMID: 35233801 PMCID: PMC9543907 DOI: 10.1002/jlb.1hi0421-181r] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 01/20/2022] [Indexed: 12/24/2022] Open
Abstract
Monocytes are mononuclear phagocytes that can differentiate to a variety of cell fates under the influence of their microenvironment and hardwired commitment. We found that inhibition of TRPM8 in human blood CD14+ monocytes during a critical 3‐h window at the beginning of their differentiation into macrophages led to enhanced survival and LPS‐driven TNFα production after 24 h. TRPM8 antagonism also promoted LPS‐driven TNFα production in CD14+ monocytes derived from the intestinal mucosa. Macrophages that had been derived for 6 days under blockade of TRPM8 had impaired phagocytic capacity and were transcriptionally distinct. Most of the affected genes were altered in a way that opposed normal monocyte to macrophage differentiation indicating that TRPM8 activity promotes aspects of this differentiation programme. Thus, we reveal a novel role for TRPM8 in regulating human CD14+ monocyte fate and function.
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Affiliation(s)
- Eve Hornsby
- Centre for Immunobiology & Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Hamish W King
- Centre for Immunobiology & Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Madusha Peiris
- Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Roberto Buccafusca
- School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London, UK
| | - Wing-Yiu Jason Lee
- Centre for Immunobiology & Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Elinor S Wing
- Centre for Immunobiology & Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - L Ashley Blackshaw
- Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - James O Lindsay
- Centre for Immunobiology & Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.,Department of Gastroenterology, Barts Health NHS Trust, The Royal London Hospital, Whitechapel, London, UK
| | - Andrew J Stagg
- Centre for Immunobiology & Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
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26
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Nguyen QV, Chong LC, Hor YY, Lew LC, Rather IA, Choi SB. Role of Probiotics in the Management of COVID-19: A Computational Perspective. Nutrients 2022; 14:274. [PMID: 35057455 PMCID: PMC8781206 DOI: 10.3390/nu14020274] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 02/01/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) was declared a pandemic at the beginning of 2020, causing millions of deaths worldwide. Millions of vaccine doses have been administered worldwide; however, outbreaks continue. Probiotics are known to restore a stable gut microbiota by regulating innate and adaptive immunity within the gut, demonstrating the possibility that they may be used to combat COVID-19 because of several pieces of evidence suggesting that COVID-19 has an adverse impact on gut microbiota dysbiosis. Thus, probiotics and their metabolites with known antiviral properties may be used as an adjunctive treatment to combat COVID-19. Several clinical trials have revealed the efficacy of probiotics and their metabolites in treating patients with SARS-CoV-2. However, its molecular mechanism has not been unraveled. The availability of abundant data resources and computational methods has significantly changed research finding molecular insights between probiotics and COVID-19. This review highlights computational approaches involving microbiome-based approaches and ensemble-driven docking approaches, as well as a case study proving the effects of probiotic metabolites on SARS-CoV-2.
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Affiliation(s)
- Quang Vo Nguyen
- Centre for Bioinformatics, School of Data Sciences, Perdana University, Suite 9.2, 9th Floor, Wisma Chase Perdana, Changkat Semantan, Wilayah Persekutuan, Kuala Lumpur 50490, Malaysia;
| | - Li Chuin Chong
- Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Beykoz, Istanbul 34820, Turkey;
| | - Yan-Yan Hor
- Department of Biotechnology, Yeungnam University, 280 Daehak-Ro, Gyeongsan 38541, Gyeongbuk, Korea;
| | - Lee-Ching Lew
- Probionic Corporation, Jeonbuk Institute for Food-Bioindustry, Jeonju 54810, Korea;
| | - Irfan A. Rather
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
- Center of Excellence in Bionanoscience Research, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
| | - Sy-Bing Choi
- Centre for Bioinformatics, School of Data Sciences, Perdana University, Suite 9.2, 9th Floor, Wisma Chase Perdana, Changkat Semantan, Wilayah Persekutuan, Kuala Lumpur 50490, Malaysia;
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27
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Wu WJH, Kim M, Chang LC, Assie A, Saldana-Morales FB, Zegarra-Ruiz DF, Norwood K, Samuel BS, Diehl GE. Interleukin-1β secretion induced by mucosa-associated gut commensal bacteria promotes intestinal barrier repair. Gut Microbes 2022; 14:2014772. [PMID: 34989321 PMCID: PMC8741296 DOI: 10.1080/19490976.2021.2014772] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 11/23/2021] [Indexed: 02/04/2023] Open
Abstract
The gut microbiota is essential for maintenance and repair of the intestinal epithelial barrier. As shifts in both intestinal epithelial barrier function and microbiota composition are found in inflammatory bowel disease patients, it is critical to understand the role of distinct bacteria in regulating barrier repair. We identified a mouse commensal E. coli isolate, GDAR2-2, that protects mice from Citrobacter rodentium infection and dextran sulfate sodium-induced colitis. Colonization with GDAR2-2 in mice resulted in expansion of CX3CR1+ mononuclear phagocytes, including CX3CR1+ macrophages/dendritic cells and monocytes, along with IL-22-secreting type 3 innate lymphoid cells and improved epithelial barrier function. In vitro co-culture of macrophages with GDAR2-2 resulted in IL-1β production. In vivo, protection after GDAR2-2 colonization was lost after depletion of CX3CR1+ MNPs, or blockade of IL-1β or IL-22. We further identified human commensal E. coli isolates that similarly protect mice from C. rodentium infection through CX3CR1+ MNP and IL-1β production. Together, these findings demonstrate an unexpected role for commensal bacteria in promoting IL-1β secretion to support intestinal barrier repair.
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Affiliation(s)
- Wan-Jung H. Wu
- Immunology Graduate Program, Baylor College of Medicine, Houston, TX, USA
- Memorial Sloan Kettering Cancer Center, Immunology Program of the Sloan Kettering Institute, New York, NY, USA
| | - Myunghoo Kim
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
- Present Address: Department of Animal Science, College of Natural Resources and Life Sciences, Pusan National University, Miryang, Korea
| | - Lin-Chun Chang
- Memorial Sloan Kettering Cancer Center, Immunology Program of the Sloan Kettering Institute, New York, NY, USA
| | - Adrien Assie
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Fatima B. Saldana-Morales
- Memorial Sloan Kettering Cancer Center, Immunology Program of the Sloan Kettering Institute, New York, NY, USA
- Neuroscience Graduate Program, Baylor College of Medicine, Houston, TX, USA
| | - Daniel F. Zegarra-Ruiz
- Memorial Sloan Kettering Cancer Center, Immunology Program of the Sloan Kettering Institute, New York, NY, USA
| | - Kendra Norwood
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Buck S. Samuel
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Gretchen E. Diehl
- Memorial Sloan Kettering Cancer Center, Immunology Program of the Sloan Kettering Institute, New York, NY, USA
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
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28
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Park Y, Zhang Q, Fernandes JMO, Wiegertjes GF, Kiron V. Macrophage Heterogeneity in the Intestinal Cells of Salmon: Hints From Transcriptomic and Imaging Data. Front Immunol 2021; 12:798156. [PMID: 35003123 PMCID: PMC8733388 DOI: 10.3389/fimmu.2021.798156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 11/24/2021] [Indexed: 11/13/2022] Open
Abstract
The intestine has many types of cells that are present mostly in the epithelium and lamina propria. The importance of the intestinal cells for the mammalian mucosal immune system is well-established. However, there is no in-depth information about many of the intestinal cells in teleosts. In our previous study, we reported that adherent intestinal cells (AIC) predominantly express macrophage-related genes. To gather further evidence that AIC include macrophage-like cells, we compared their phagocytic activity and morphology with those of adherent head kidney cells (AKC), previously characterized as macrophage-like cells. We also compared equally abundant as well as differentially expressed mRNAs and miRNAs between AIC and AKC. AIC had lower phagocytic activity and were larger and more circular than macrophage-like AKC. RNA-Seq data revealed that there were 18309 mRNAs, with 59 miRNAs that were equally abundant between AIC and AKC. Integrative analysis of the mRNA and miRNA transcriptomes revealed macrophage heterogeneity in both AIC and AKC. In addition, analysis of AIC and AKC transcriptomes revealed functional characteristics of mucosal and systemic macrophages. Five pairs with significant negative correlations between miRNA and mRNAs were linked to macrophages and epithelial cells and their interaction could be pointing to macrophage activation and differentiation. The potential macrophage markers suggested in this study should be investigated under different immune conditions to understand the exact macrophage phenotypes.
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Affiliation(s)
- Youngjin Park
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Qirui Zhang
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | | | - Geert F. Wiegertjes
- Aquaculture and Fisheries Group, Wageningen University & Research, Wageningen, Netherlands
| | - Viswanath Kiron
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
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29
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Lu L, Liu YJ, Cheng PQ, Hu D, Xu HC, Ji G. Macrophages play a role in inflammatory transformation of colorectal cancer. World J Gastrointest Oncol 2021; 13:2013-2028. [PMID: 35070038 PMCID: PMC8713318 DOI: 10.4251/wjgo.v13.i12.2013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/21/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide, and it is also a typical inflammatory cancer. The function of macrophages is very important in the tissue immune microenvironment during inflammatory and carcinogenic transformation. Here, we evaluated the function and mechanism of macrophages in intestinal physiology and in different pathological stages. Furthermore, the role of macrophages in the immune microenvironment of CRC and the influence of the intestinal population and hypoxic environment on macrophage function are summarized. In addition, in the era of tumor immunotherapy, CRC currently has a limited response rate to immune checkpoint inhibitors, and we summarize potential therapeutic strategies for targeting tumor-associated macrophages.
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Affiliation(s)
- Lu Lu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yu-Jing Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Pei-Qiu Cheng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Dan Hu
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China
| | - Han-Chen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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30
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Hentschel V, Seufferlein T, Armacki M. Intestinal organoids in coculture: redefining the boundaries of gut mucosa ex vivo modeling. Am J Physiol Gastrointest Liver Physiol 2021; 321:G693-G704. [PMID: 34643092 DOI: 10.1152/ajpgi.00043.2021] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
All-time preservation of an intact mucosal barrier is crucial to ensuring intestinal homeostasis and, hence, the organism's overall health maintenance. This complex process relies on an equilibrated signaling system between the intestinal epithelium and numerous cell populations inhabiting the gut mucosa. Any perturbations of this delicate cross talk, particularly regarding the immune cell compartment and microbiota, may sustainably debilitate the intestinal barrier function. As a final joint event, a critical rise in epithelial permeability facilitates the exposure of submucosal immunity to microbial antigens, resulting in uncontrolled inflammation, collateral tissue destruction, and dysbiosis. Organoid-derived intestinal coculture models have established themselves as convenient tools to reenact such pathophysiological events, explore interactions between selected cell populations, and assess their roles with a central focus on intestinal barrier recovery and stabilization.
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Affiliation(s)
- Viktoria Hentschel
- Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
| | - Thomas Seufferlein
- Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
| | - Milena Armacki
- Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
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31
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Hausmann A, Felmy B, Kunz L, Kroon S, Berthold DL, Ganz G, Sandu I, Nakamura T, Zangger NS, Zhang Y, Dolowschiak T, Fattinger SA, Furter M, Müller-Hauser AA, Barthel M, Vlantis K, Wachsmuth L, Kisielow J, Tortola L, Heide D, Heikenwälder M, Oxenius A, Kopf M, Schroeder T, Pasparakis M, Sellin ME, Hardt WD. Intercrypt sentinel macrophages tune antibacterial NF-κB responses in gut epithelial cells via TNF. J Exp Med 2021; 218:e20210862. [PMID: 34529751 PMCID: PMC8480669 DOI: 10.1084/jem.20210862] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 07/21/2021] [Accepted: 08/25/2021] [Indexed: 12/14/2022] Open
Abstract
Intestinal epithelial cell (IEC) NF-κB signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-κB activation in vivo. However, we found that in mice, IECs do not respond directly to LPS. Instead, tissue-resident lamina propria intercrypt macrophages sense LPS via TLR4 and rapidly secrete TNF to elicit epithelial NF-κB signaling in their immediate neighborhood. This response pattern is relevant also during oral enteropathogen infection. The macrophage-TNF-IEC axis avoids responses to luminal microbiota LPS but enables crypt- or tissue-scale epithelial NF-κB responses in proportion to the microbial threat. Thereby, intercrypt macrophages fulfill important sentinel functions as first responders to Gram-negative microbes breaching the epithelial barrier. The tunability of this crypt response allows the induction of defense mechanisms at an appropriate scale according to the localization and intensity of microbial triggers.
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Affiliation(s)
- Annika Hausmann
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Boas Felmy
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Leo Kunz
- Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zurich, Basel, Switzerland
| | - Sanne Kroon
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Dorothée Lisa Berthold
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Giverny Ganz
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Ioana Sandu
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Toshihiro Nakamura
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Nathan Sébastien Zangger
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Yang Zhang
- Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zurich, Basel, Switzerland
| | - Tamas Dolowschiak
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Stefan Alexander Fattinger
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Markus Furter
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Anna Angelika Müller-Hauser
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Manja Barthel
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Katerina Vlantis
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
| | - Laurens Wachsmuth
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
| | - Jan Kisielow
- Institute of Molecular Health Sciences, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Luigi Tortola
- Institute of Molecular Health Sciences, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Danijela Heide
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Annette Oxenius
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Manfred Kopf
- Institute of Molecular Health Sciences, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
| | - Timm Schroeder
- Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zurich, Basel, Switzerland
| | - Manolis Pasparakis
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
| | - Mikael Erik Sellin
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Wolf-Dietrich Hardt
- Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland
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Ghosh S, Pramanik S. Structural diversity, functional aspects and future therapeutic applications of human gut microbiome. Arch Microbiol 2021; 203:5281-5308. [PMID: 34405262 PMCID: PMC8370661 DOI: 10.1007/s00203-021-02516-y] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/29/2021] [Accepted: 08/06/2021] [Indexed: 02/06/2023]
Abstract
The research on human gut microbiome, regarded as the black box of the human body, is still at the stage of infancy as the functional properties of the complex gut microbiome have not yet been understood. Ongoing metagenomic studies have deciphered that the predominant microbial communities belong to eubacterial phyla Firmicutes, Bacteroidetes, Proteobacteria, Fusobacteria, Cyanobacteria, Verrucomicrobia and archaebacterial phylum Euryarchaeota. The indigenous commensal microbial flora prevents opportunistic pathogenic infection and play undeniable roles in digestion, metabolite and signaling molecule production and controlling host's cellular health, immunity and neuropsychiatric behavior. Besides maintaining intestinal health via short-chain fatty acid (SCFA) production, gut microbes also aid in neuro-immuno-endocrine modulatory molecule production, immune cell differentiation and glucose and lipid metabolism. Interdependence of diet and intestinal microbial diversity suggests the effectiveness of pre- and pro-biotics in maintenance of gut and systemic health. Several companies worldwide have started potentially exploiting the microbial contribution to human health and have translated their use in disease management and therapeutic applications. The present review discusses the vast diversity of microorganisms playing intricate roles in human metabolism. The contribution of the intestinal microbiota to regulate systemic activities including gut-brain-immunity crosstalk has been focused. To the best of our knowledge, this review is the first of its kind to collate and discuss the companies worldwide translating the multi-therapeutic potential of human intestinal microbiota, based on the multi-omics studies, i.e. metagenomics and metabolomics, as ready solutions for several metabolic and systemic disorders.
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Affiliation(s)
- Soma Ghosh
- Kolkata Zonal Center, CSIR-National Environmental Engineering Research Institute, i-8 Sector-C, East Kolkata Township, Kolkata, 700107, India.
| | - Sreemanta Pramanik
- Kolkata Zonal Center, CSIR-National Environmental Engineering Research Institute, i-8 Sector-C, East Kolkata Township, Kolkata, 700107, India
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Chiaranunt P, Tai SL, Ngai L, Mortha A. Beyond Immunity: Underappreciated Functions of Intestinal Macrophages. Front Immunol 2021; 12:749708. [PMID: 34650568 PMCID: PMC8506163 DOI: 10.3389/fimmu.2021.749708] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal tract hosts the largest compartment of macrophages in the body, where they serve as mediators of host defense and immunity. Seeded in the complex tissue-environment of the gut, an array of both hematopoietic and non-hematopoietic cells forms their immediate neighborhood. Emerging data demonstrate that the functional diversity of intestinal macrophages reaches beyond classical immunity and includes underappreciated non-immune functions. In this review, we discuss recent advances in research on intestinal macrophage heterogeneity, with a particular focus on how non-immune functions of macrophages impact tissue homeostasis and function. We delve into the strategic localization of distinct gut macrophage populations, describe the potential factors that regulate their identity and functional heterogeneity within these locations, and provide open questions that we hope will inspire research dedicated to elucidating a holistic view on macrophage-tissue cell interactions in the body's largest mucosal organ.
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Affiliation(s)
- Pailin Chiaranunt
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Siu Ling Tai
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Louis Ngai
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Arthur Mortha
- Department of Immunology, University of Toronto, Toronto, ON, Canada
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Wright PB, McDonald E, Bravo-Blas A, Baer HM, Heawood A, Bain CC, Mowat AM, Clay SL, Robertson EV, Morton F, Nijjar JS, Ijaz UZ, Milling SWF, Gaya DR. The mannose receptor (CD206) identifies a population of colonic macrophages in health and inflammatory bowel disease. Sci Rep 2021; 11:19616. [PMID: 34608184 PMCID: PMC8490356 DOI: 10.1038/s41598-021-98611-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
To understand the contribution of mononuclear phagocytes (MNP), which include monocyte-derived intestinal macrophages, to the pathogenesis of inflammatory bowel disease (IBD), it is necessary to identify functionally-different MNP populations. We aimed to characterise intestinal macrophage populations in patients with IBD. We developed 12-parameter flow cytometry protocols to identify and human intestinal MNPs. We used these protocols to purify and characterize colonic macrophages from colonic tissue from patients with Crohn’s disease (CD), ulcerative colitis (UC), or non-inflamed controls, in a cross-sectional study. We identify macrophage populations (CD45+CD64+ HLA-DR+) and describe two distinct subsets, differentiated by their expression of the mannose receptor, CD206. CD206+ macrophages expressed markers consistent with a mature phenotype: high levels of CD68 and CD163, higher transcription of IL-10 and lower expression of TREM1. CD206− macrophages appear to be less mature, with features more similar to their monocytic precursors. We identified and purified macrophage populations from human colon. These appear to be derived from a monocytic precursor with high CCR2 and low CD206 expression. As these cells mature, they acquire expression of IL-10, CD206, CD63, and CD168. Targeting the newly recruited monocyte-derived cells may represent a fruitful avenue to ameliorate chronic inflammation in IBD.
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Affiliation(s)
- Pamela B Wright
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK
| | - Elizabeth McDonald
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK
| | - Alberto Bravo-Blas
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK
| | - Hannah M Baer
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK
| | - Anna Heawood
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK
| | - Calum C Bain
- MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Allan M Mowat
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK
| | - Slater L Clay
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK
| | | | - Fraser Morton
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK
| | - Jagtar Singh Nijjar
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK
| | - Umer Z Ijaz
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK
| | - Simon W F Milling
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
| | - Daniel R Gaya
- Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, UK
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Yip JL, Balasuriya GK, Spencer SJ, Hill-Yardin EL. The Role of Intestinal Macrophages in Gastrointestinal Homeostasis: Heterogeneity and Implications in Disease. Cell Mol Gastroenterol Hepatol 2021; 12:1701-1718. [PMID: 34506953 PMCID: PMC8551786 DOI: 10.1016/j.jcmgh.2021.08.021] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 12/13/2022]
Abstract
Intestinal macrophages play a key role in the gut immune system and the regulation of gastrointestinal physiology, including gut motility and secretion. Their ability to keep the gut from chronic inflammation despite constantly facing foreign antigens has been an important focus in gastrointestinal research. However, the heterogeneity of intestinal macrophages has impeded our understanding of their specific roles. It is now becoming clear that subsets of intestinal macrophages play diverse roles in various gastrointestinal diseases. This occurs through a complex interplay between cytokine production and enteric nervous system activation that differs for each pathologic condition. Key diseases and disorders in which intestinal macrophages play a role include postoperative ileus, inflammatory bowel disease, necrotizing enterocolitis, as well as gastrointestinal disorders associated with human immunodeficiency virus and Parkinson's disease. Here, we review the identification of intestinal macrophage subsets based on their origins and functions, how specific subsets regulate gut physiology, and the potential for these heterogeneous subpopulations to contribute to disease states. Furthermore, we outline the potential for these subpopulations to provide unique targets for the development of novel therapies for these disorders.
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Affiliation(s)
| | | | - Sarah J. Spencer
- School of Health and Biomedical Sciences,Australian Research Council Centre of Excellence for Nanoscale Biophotonics, Royal Melbourne Instutite of Technology, Melbourne, Victoria, Australia
| | - Elisa L. Hill-Yardin
- School of Health and Biomedical Sciences,Correspondence Address correspondence to: Elisa L. Hill-Yardin, PhD, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia.
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36
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Ranjan K, Hedl M, Sinha S, Zhang X, Abraham C. Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor-induced unfolded protein response. J Clin Invest 2021; 131:e145472. [PMID: 34623328 PMCID: PMC8409591 DOI: 10.1172/jci145472] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 07/20/2021] [Indexed: 02/05/2023] Open
Abstract
Properly balancing microbial responses by the innate immune system through pattern recognition receptors (PRRs) is critical for intestinal immune homeostasis. Ring finger protein 186 (RNF186) genetic variants are associated with inflammatory bowel disease (IBD). However, functions for the E3 ubiquitin ligase RNF186 are incompletely defined. We found that upon stimulation of the PRR nucleotide-binding oligomerization domain containing 2 (NOD2) in human macrophages, RNF186 localized to the ER, formed a complex with ER stress sensors, ubiquitinated the ER stress sensor activating transcription factor 6 (ATF6), and promoted the unfolded protein response (UPR). These events, in turn, led to downstream signaling, cytokine secretion, and antimicrobial pathway induction. Importantly, RNF186-mediated ubiquitination of K152 on ATF6 was required for these outcomes, highlighting a key role for ATF6 ubiquitination in PRR-initiated functions. Human macrophages transfected with the rare RNF186-A64T IBD risk variant and macrophages from common rs6426833 RNF186 IBD risk carriers demonstrated reduced NOD2-induced outcomes, which were restored by rescuing UPR signaling. Mice deficient in RNF186 or ATF6 demonstrated a reduced UPR in colonic tissues, increased weight loss, and less effective clearance of bacteria with dextran sodium sulfate-induced injury and upon oral challenge with Salmonella Typhimurium. Therefore, we identified that RNF186 was required for PRR-induced, UPR-associated signaling leading to key macrophage functions; defined that RNF186-mediated ubiquitination of ATF6 was essential for these functions; and elucidated how RNF186 IBD risk variants modulated these outcomes.
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Affiliation(s)
- Kishu Ranjan
- Department of Internal Medicine, Section of Digestive Diseases, and
| | - Matija Hedl
- Department of Internal Medicine, Section of Digestive Diseases, and
| | - Saloni Sinha
- Department of Internal Medicine, Section of Digestive Diseases, and
| | - Xuchen Zhang
- Department of Pathology, Yale University, New Haven, Connecticut, USA
| | - Clara Abraham
- Department of Internal Medicine, Section of Digestive Diseases, and
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37
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Role of macrophages in fetal development and perinatal disorders. Pediatr Res 2021; 90:513-523. [PMID: 33070164 DOI: 10.1038/s41390-020-01209-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/17/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023]
Abstract
In the fetus and the neonate, altered macrophage function has been implicated not only in inflammatory disorders but also in developmental abnormalities marked by altered onset, interruption, or imbalance of key structural changes. The developmental role of macrophages were first noted nearly a century ago, at about the same time when these cells were being identified as central effectors in phagocytosis and elimination of microbes. Since that time, we have made considerable progress in understanding the diverse roles that these cells play in both physiology and disease. Here, we review the role of fetal and neonatal macrophages in immune surveillance, innate immunity, homeostasis, tissue remodeling, angiogenesis, and repair of damaged tissues. We also discuss the possibility of therapeutic manipulation of the relative abundance and activation status of macrophage subsets in various diseases. This article combines peer-reviewed evidence from our own studies with results of an extensive literature search in the databases PubMed, EMBASE, and Scopus. IMPACT: We have reviewed the structure, differentiation, and classification of macrophages in the neonatal period. Neonatal macrophages are derived from embryonic, hepatic, and bone marrow precursors. Macrophages play major roles in tissue homeostasis, innate immunity, inflammation, tissue repair, angiogenesis, and apoptosis of various cellular lineages in various infectious and inflammatory disorders. Macrophages and related inflammatory mediators could be important therapeutic targets in several neonatal diseases.
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38
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Johnson SD, Olwenyi OA, Bhyravbhatla N, Thurman M, Pandey K, Klug EA, Johnston M, Dyavar SR, Acharya A, Podany AT, Fletcher CV, Mohan M, Singh K, Byrareddy SN. Therapeutic implications of SARS-CoV-2 dysregulation of the gut-brain-lung axis. World J Gastroenterol 2021; 27:4763-4783. [PMID: 34447225 PMCID: PMC8371510 DOI: 10.3748/wjg.v27.i29.4763] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/10/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
The emergence and rapid spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 180 million confirmed cases resulting in over 4 million deaths worldwide with no clear end in sight for the coronavirus disease 19 (COVID-19) pandemic. Most SARS-CoV-2 exposed individuals experience mild to moderate symptoms, including fever, cough, fatigue, and loss of smell and taste. However, many individuals develop pneumonia, acute respiratory distress syndrome, septic shock, and multiorgan dysfunction. In addition to these primarily respiratory symptoms, SARS-CoV-2 can also infiltrate the central nervous system, which may damage the blood-brain barrier and the neuron's synapses. Resultant inflammation and neurodegeneration in the brain stem can further prevent efferent signaling to cranial nerves, leading to the loss of anti-inflammatory signaling and normal respiratory and gastrointestinal functions. Additionally, SARS-CoV-2 can infect enterocytes resulting in gut damage followed by microbial dysbiosis and translocation of bacteria and their byproducts across the damaged epithelial barrier. As a result, this exacerbates pro-inflammatory responses both locally and systemically, resulting in impaired clinical outcomes. Recent evidence has highlighted the complex interactions that mutually modulate respiratory, neurological, and gastrointestinal function. In this review, we discuss the ways SARS-CoV-2 potentially disrupts the gut-brain-lung axis. We further highlight targeting specific responses to SARS-CoV-2 for the development of novel, urgently needed therapeutic interventions. Finally, we propose a prospective related to the individuals from Low- and Middle-Income countries. Here, the underlying propensity for heightened gut damage/microbial translocation is likely to result in worse clinical outcomes during this COVID-19 pandemic.
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Affiliation(s)
- Samuel D Johnson
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Omalla A Olwenyi
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Namita Bhyravbhatla
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Michellie Thurman
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kabita Pandey
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Elizabeth A Klug
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Morgan Johnston
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Shetty Ravi Dyavar
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Arpan Acharya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Anthony T Podany
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Courtney V Fletcher
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Mahesh Mohan
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, United States
| | - Kamal Singh
- Department of Molecular Microbiology and Immunology and Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, United States
| | - Siddappa N Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States
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Mertens C, Marques O, Horvat NK, Simonetti M, Muckenthaler MU, Jung M. The Macrophage Iron Signature in Health and Disease. Int J Mol Sci 2021; 22:ijms22168457. [PMID: 34445160 PMCID: PMC8395084 DOI: 10.3390/ijms22168457] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 12/13/2022] Open
Abstract
Throughout life, macrophages are located in every tissue of the body, where their main roles are to phagocytose cellular debris and recycle aging red blood cells. In the tissue niche, they promote homeostasis through trophic, regulatory, and repair functions by responding to internal and external stimuli. This in turn polarizes macrophages into a broad spectrum of functional activation states, also reflected in their iron-regulated gene profile. The fast adaptation to the environment in which they are located helps to maintain tissue homeostasis under physiological conditions.
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Affiliation(s)
- Christina Mertens
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany; (O.M.); (N.K.H.); (M.U.M.)
- Correspondence: (C.M.); (M.J.); Tel.: +(49)-622-156-4582 (C.M.); +(49)-696-301-6931 (M.J.)
| | - Oriana Marques
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany; (O.M.); (N.K.H.); (M.U.M.)
- Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
| | - Natalie K. Horvat
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany; (O.M.); (N.K.H.); (M.U.M.)
- Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), Collaboration for Joint PhD Degree between EMBL and the Faculty of Biosciences, University of Heidelberg, 69117 Heidelberg, Germany
| | - Manuela Simonetti
- Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University, INF 366, 69120 Heidelberg, Germany;
| | - Martina U. Muckenthaler
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany; (O.M.); (N.K.H.); (M.U.M.)
- Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
| | - Michaela Jung
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
- Correspondence: (C.M.); (M.J.); Tel.: +(49)-622-156-4582 (C.M.); +(49)-696-301-6931 (M.J.)
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40
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The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes. Proc Natl Acad Sci U S A 2021; 118:2013500118. [PMID: 34353900 DOI: 10.1073/pnas.2013500118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Balancing microbial-induced cytokines and microbial clearance is critical at mucosal sites such as the intestine. How the inflammatory bowel disease (IBD)-associated gene RNF186 regulates this balance is unclear. We found that macrophages from IBD-risk rs6426833 carriers in the RNF186 region showed reduced cytokines to stimulation through multiple pattern recognition receptors (PRRs). Upon stimulation of PRRs, the E3-ubiquitin ligase RNF186 promoted ubiquitination of signaling complex molecules shared across PRRs and those unique to select PRRs. Furthermore, RNF186 was required for PRR-initiated signaling complex assembly and downstream signaling. RNF186, along with its intact E3-ubiquitin ligase activity, was required for optimal PRR-induced antimicrobial reactive oxygen species, reactive nitrogen species, and autophagy pathways and intracellular bacterial clearance in human macrophages and for bacterial clearance in intestinal myeloid cells. Cells transfected with the rare RNF186-A64T IBD-risk variant and macrophages from common rs6426833 RNF186 IBD-risk carriers demonstrated a reduction in these RNF186-dependent outcomes. These studies identify mechanisms through which RNF186 regulates innate immunity and show that RNF186 IBD-risk variants demonstrate a loss of function in PRR-initiated outcomes.
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41
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Varga-Medveczky Z, Kovács N, Tóth ME, Sántha M, Horváth I, Bors LA, Fónagy K, Imre T, Szabó P, Máthé D, Erdő F. Age-Related Inflammatory Balance Shift, Nasal Barrier Function, and Cerebro-Morphological Status in Healthy and Diseased Rodents. Front Neurosci 2021; 15:700729. [PMID: 34366780 PMCID: PMC8343234 DOI: 10.3389/fnins.2021.700729] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/14/2021] [Indexed: 01/20/2023] Open
Abstract
Increased blood–brain barrier (BBB) permeability and extensive neuronal changes have been described earlier in both healthy and pathological aging like apolipoprotein B-100 (APOB-100) and amyloid precursor protein (APP)–presenilin-1 (PSEN1) transgenic mouse models. APOB-100 hypertriglyceridemic model is a useful tool to study the link between cerebrovascular pathology and neurodegeneration, while APP–PSEN1 humanized mouse is a model of Alzheimer’s disease. The aim of the current study was to characterize the inflammatory changes in the brain with healthy aging and in neurodegeneration. Also, the cerebro-morphological and cognitive alterations have been investigated. The nose-to-brain delivery of a P-glycoprotein substrate model drug (quinidine) was monitored in the disease models and compared with the age-matched controls. Our results revealed an inflammatory balance shift in both the healthy aged and neurodegenerative models. In normal aging monocyte chemoattractant protein-1, stem cell factor and Rantes were highly upregulated indicating a stimulated leukocyte status. In APOB-100 mice, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF-BB), and interleukin-17A (IL-17A) were induced (vascular reaction), while in APP–PSEN1 mice resistin, IL-17A and GM-CSF were mostly upregulated. The nasal drug absorption was similar in the brain and blood indicating the molecular bypass of the BBB. The learning and memory tests showed no difference in the cognitive performance of healthy aged and young animals. Based on these results, it can be concluded that various markers of chronic inflammation are present in healthy aged and diseased animals. In APOB-100 mice, a cerebro-ventricular dilation can also be observed. For development of proper anti-aging and neuroprotective compounds, further studies focusing on the above inflammatory targets are suggested.
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Affiliation(s)
- Zsófia Varga-Medveczky
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
| | - Noémi Kovács
- Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Melinda E Tóth
- Institute of Biochemistry, ELKH Biological Research Centre, Szeged, Hungary
| | - Miklós Sántha
- Institute of Biochemistry, ELKH Biological Research Centre, Szeged, Hungary
| | - Ildikó Horváth
- Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Luca Anna Bors
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary.,Heart and Vascular Centre, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Katalin Fónagy
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
| | - Timea Imre
- Research Centre for Natural Sciences, Centre for Structural Study, Budapest, Hungary
| | - Pál Szabó
- Research Centre for Natural Sciences, Centre for Structural Study, Budapest, Hungary
| | - Domokos Máthé
- Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.,Hungarian Center of Excellence for Molecular Medicine (HCEMM), Advanced In Vivo Imaging Core Faciltiy, Budapest, Hungary
| | - Franciska Erdő
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
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Pensado-López A, Fernández-Rey J, Reimunde P, Crecente-Campo J, Sánchez L, Torres Andón F. Zebrafish Models for the Safety and Therapeutic Testing of Nanoparticles with a Focus on Macrophages. NANOMATERIALS 2021; 11:nano11071784. [PMID: 34361170 PMCID: PMC8308170 DOI: 10.3390/nano11071784] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/05/2021] [Accepted: 07/07/2021] [Indexed: 12/11/2022]
Abstract
New nanoparticles and biomaterials are increasingly being used in biomedical research for drug delivery, diagnostic applications, or vaccines, and they are also present in numerous commercial products, in the environment and workplaces. Thus, the evaluation of the safety and possible therapeutic application of these nanomaterials has become of foremost importance for the proper progress of nanotechnology. Due to economical and ethical issues, in vitro and in vivo methods are encouraged for the testing of new compounds and/or nanoparticles, however in vivo models are still needed. In this scenario, zebrafish (Danio rerio) has demonstrated potential for toxicological and pharmacological screenings. Zebrafish presents an innate immune system, from early developmental stages, with conserved macrophage phenotypes and functions with respect to humans. This fact, combined with the transparency of zebrafish, the availability of models with fluorescently labelled macrophages, as well as a broad variety of disease models offers great possibilities for the testing of new nanoparticles. Thus, with a particular focus on macrophage-nanoparticle interaction in vivo, here, we review the studies using zebrafish for toxicological and biodistribution testing of nanoparticles, and also the possibilities for their preclinical evaluation in various diseases, including cancer and autoimmune, neuroinflammatory, and infectious diseases.
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Affiliation(s)
- Alba Pensado-López
- Department of Zoology, Genetics and Physical Anthropology, Campus de Lugo, Universidade de Santiago de Compostela, 27002 Lugo, Spain; (A.P.-L.); (J.F.-R.)
- Center for Research in Molecular Medicine & Chronic Diseases (CIMUS), Campus Vida, Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain;
| | - Juan Fernández-Rey
- Department of Zoology, Genetics and Physical Anthropology, Campus de Lugo, Universidade de Santiago de Compostela, 27002 Lugo, Spain; (A.P.-L.); (J.F.-R.)
- Center for Research in Molecular Medicine & Chronic Diseases (CIMUS), Campus Vida, Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain;
| | - Pedro Reimunde
- Department of Physiotherapy, Medicine and Biomedical Sciences, Universidade da Coruña, Campus de Oza, 15006 A Coruña, Spain;
- Department of Neurosurgery, Hospital Universitario Lucus Augusti, 27003 Lugo, Spain
| | - José Crecente-Campo
- Center for Research in Molecular Medicine & Chronic Diseases (CIMUS), Campus Vida, Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain;
| | - Laura Sánchez
- Department of Zoology, Genetics and Physical Anthropology, Campus de Lugo, Universidade de Santiago de Compostela, 27002 Lugo, Spain; (A.P.-L.); (J.F.-R.)
- Correspondence: (L.S.); (F.T.A.)
| | - Fernando Torres Andón
- Center for Research in Molecular Medicine & Chronic Diseases (CIMUS), Campus Vida, Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain;
- Correspondence: (L.S.); (F.T.A.)
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Rajput S, Paliwal D, Naithani M, Kothari A, Meena K, Rana S. COVID-19 and Gut Microbiota: A Potential Connection. Indian J Clin Biochem 2021; 36:266-277. [PMID: 33495676 PMCID: PMC7818076 DOI: 10.1007/s12291-020-00948-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023]
Abstract
Currently, world is facing a global outbreak causing a pandemic threat known as COVID-19. This infectious disease is triggered by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Gut microbiota harbours multi species community with a strong impact on host immune homeostasis. However, our knowledge about this gut microbiota and its symbiotic relationship with immune activation in association with SARS-CoV-2 is limited. Unbalanced bacterial flora with too many opportunistic infections can shift immune system towards a cascade of inflammatory responses leading to multi organ damage. This review will highlight immune-regulation via various mechanisms in SARS-CoV-2 infection. Diet has an unbelievable influence on gut microbiome that allows a new state of homeostasis to be reached through timing, frequency and duration of intake. This review article focuses on gut, lung microbiota and immunomodulation with specific attention on immune activation by gut microbiota.
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Affiliation(s)
- Swati Rajput
- Department of Biochemistry, AIIMS Rishikesh, Uttarakhand, 249203 India
| | - Deepanshu Paliwal
- Department of Biochemistry, AIIMS Rishikesh, Uttarakhand, 249203 India
| | - Manisha Naithani
- Department of Biochemistry, AIIMS Rishikesh, Uttarakhand, 249203 India
| | - Aashish Kothari
- Department of Microbiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand India
| | - Kiran Meena
- Department of Biochemistry, AIIMS Rishikesh, Uttarakhand, 249203 India
| | - Satyavati Rana
- Department of Biochemistry, AIIMS Rishikesh, Uttarakhand, 249203 India
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Maasfeh L, Härtlova A, Isaksson S, Sundin J, Mavroudis G, Savolainen O, Strid H, Öhman L, Magnusson MK. Impaired Luminal Control of Intestinal Macrophage Maturation in Patients With Ulcerative Colitis During Remission. Cell Mol Gastroenterol Hepatol 2021; 12:1415-1432. [PMID: 34126236 PMCID: PMC8479254 DOI: 10.1016/j.jcmgh.2021.06.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 06/08/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Intestinal macrophages adopt a hyporesponsive phenotype through education by local signals. Lack of proper macrophage maturation in patients with ulcerative colitis (UC) in remission may initiate gut inflammation. The aim, therefore, was to determine the effects of fecal luminal factors derived from healthy donors and UC patients in remission on macrophage phenotype and function. METHODS Fecal supernatants (FS) were extracted from fecal samples of healthy subjects and UC patients in remission. Monocytes were matured into macrophages in the presence of granulocyte-macrophage colony-stimulating factor without/with FS, stimulated with lipopolysaccharide, and macrophage phenotype and function were assessed. Fecal metabolomic profiles were analyzed by gas-chromatography/mass-spectrometry. RESULTS Fecal luminal factors derived from healthy donors were effective in down-regulating Toll-like receptor signaling, cytokine signaling, and antigen presentation in macrophages. Fecal luminal factors derived from UC patients in remission were less potent in inducing lipopolysaccharide hyporesponsiveness and modulating expression of genes involved in macrophage cytokine and Toll-like receptor signaling pathways. Although phagocytic and bactericidal abilities of macrophages were not affected by FS treatment, healthy FS-treated macrophages showed a greater ability to suppress cluster of differentiation 4+ T-cell activation and interferon γ secretion compared with UC remission FS-treated counterparts. Furthermore, metabolomic analysis showed differential fecal metabolite composition for healthy donors and UC patients in remission. CONCLUSIONS Our data indicate that UC patients in remission lack luminal signals able to condition macrophages toward a hyporesponsive and tolerogenic phenotype, which may contribute to their persistent vulnerability to relapse.
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Affiliation(s)
- Lujain Maasfeh
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anetta Härtlova
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,Wallenberg Centre for Molecular and Translational Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Stefan Isaksson
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Johanna Sundin
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,Department of Internal Medicine and Clinical Nutrition, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | - Otto Savolainen
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Hans Strid
- Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden
| | - Lena Öhman
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maria K. Magnusson
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,Correspondence Address correspondence to: Maria K. Magnusson, PhD, Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Box 435, 405 30 Gothenburg, Sweden. fax: (46) 31-786 6210
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Rohm TV, Fuchs R, Müller RL, Keller L, Baumann Z, Bosch AJT, Schneider R, Labes D, Langer I, Pilz JB, Niess JH, Delko T, Hruz P, Cavelti-Weder C. Obesity in Humans Is Characterized by Gut Inflammation as Shown by Pro-Inflammatory Intestinal Macrophage Accumulation. Front Immunol 2021; 12:668654. [PMID: 34054838 PMCID: PMC8158297 DOI: 10.3389/fimmu.2021.668654] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/26/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic low-grade inflammation is a hallmark of obesity and associated with cardiovascular complications. However, it remains unclear where this inflammation starts. As the gut is constantly exposed to food, gut microbiota, and metabolites, we hypothesized that mucosal immunity triggers an innate inflammatory response in obesity. We characterized five distinct macrophage subpopulations (P1-P5) along the gastrointestinal tract and blood monocyte subpopulations (classical, non-classical, intermediate), which replenish intestinal macrophages, in non-obese (BMI<27kg/m2) and obese individuals (BMI>32kg/m2). To elucidate factors that potentially trigger gut inflammation, we correlated these subpopulations with cardiovascular risk factors and lifestyle behaviors. In obese individuals, we found higher pro-inflammatory macrophages in the stomach, duodenum, and colon. Intermediate blood monocytes were also increased in obesity, suggesting enhanced recruitment to the gut. We identified unhealthy lifestyle habits as potential triggers of gut and systemic inflammation (i.e., low vegetable intake, high processed meat consumption, sedentary lifestyle). Cardiovascular risk factors other than body weight did not affect the innate immune response. Thus, obesity in humans is characterized by gut inflammation as shown by accumulation of pro-inflammatory intestinal macrophages, potentially via recruited blood monocytes. Understanding gut innate immunity in human obesity might open up new targets for immune-modulatory treatments in metabolic disease.
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Affiliation(s)
- Theresa V Rohm
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Regula Fuchs
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland
| | - Rahel L Müller
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland
| | - Lena Keller
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Zora Baumann
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Department of Surgery, University Hospital Basel, Basel, Switzerland
| | - Angela J T Bosch
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Romano Schneider
- Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases Basel, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Danny Labes
- Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Igor Langer
- Department of Visceral Surgery, Lindenhof Hospital, Bern, Switzerland
| | - Julia B Pilz
- AMB-Arztpraxis MagenDarm Basel, Basel and MagenDarm Aarau, Aarau, Switzerland
| | - Jan H Niess
- Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases Basel, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Tarik Delko
- Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases Basel, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Petr Hruz
- Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases Basel, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Claudia Cavelti-Weder
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
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Wu MY, Liu L, Wang EJ, Xiao HT, Cai CZ, Wang J, Su H, Wang Y, Tan J, Zhang Z, Wang J, Yao M, Ouyang DF, Yue Z, Li M, Chen Y, Bian ZX, Lu JH. PI3KC3 complex subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation. Autophagy 2021; 17:1096-1111. [PMID: 32160108 PMCID: PMC8143223 DOI: 10.1080/15548627.2020.1741332] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 03/04/2020] [Accepted: 03/09/2020] [Indexed: 12/13/2022] Open
Abstract
NRBF2, a regulatory subunit of the ATG14-BECN1/Beclin 1-PIK3C3/VPS34 complex, positively regulates macroautophagy/autophagy. In this study, we report that NRBF2 is required for the clearance of apoptotic cells and alleviation of inflammation during colitis in mice. NRBF2-deficient mice displayed much more severe colitis symptoms after the administration of ulcerative colitis inducer, dextran sulfate sodium salt (DSS), accompanied by prominent intestinal inflammation and apoptotic cell accumulation. Interestingly, we found that nrbf2-/- mice and macrophages displayed impaired apoptotic cell clearance capability, while adoptive transfer of nrbf2+/+ macrophages to nrbf2-/- mice alleviated DSS-induced colitis lesions. Mechanistically, NRBF2 is required for the generation of the active form of RAB7 to promote the fusion between phagosomes containing engulfed apoptotic cells and lysosomes via interacting with the MON1-CCZ1 complex and regulating the guanine nucleotide exchange factor (GEF) activity of the complex. Evidence from clinical samples further reveals the physiological role of NRBF2 in maintaining intestinal homeostasis. In biopsies of UC patient colon, we observed upregulated NRBF2 in the colon macrophages and the engulfment of apoptotic cells by NRBF2-positive cells, suggesting a potential protective role for NRBF2 in UC. To confirm the relationship between apoptotic cell clearance and IBD development, we compared TUNEL-stained cell counts in the UC with UC severity (Mayo Score) and observed a strong correlation between the two indexes, indicating that apoptotic cell population in colon tissue correlates with UC severity. The findings of our study reveal a novel role for NRBF2 in regulating apoptotic cell clearance to restrict intestinal inflammation.Abbreviation: ANOVA: analysis of variance; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BMDM: bone marrow-derived macrophage; BSA: bovine serum albumin; CD: Crohn disease; CD68: CD68 molecule; CFP: cyan fluorescent protein; CMFDA: 5-chloromethylfluorescein diacetate; Co-IP, co-immunoprecipitation; CPR: C-reactive protein; Cy7: cyanine 7 maleimide; DAB: diaminobezidine 3; DAI: disease activity indexes; DAPI: 4'6-diamidino-2-phenylindole; DMEM: dulbecco's modified eagle's medium; DMSO: dimethyl sulfoxide; DOC: sodium deoxycholate; DSS: dextran sulfate sodium; EDTA: ethylenediaminetetraacetic acid; EGTA: ethylenebis (oxyethylenenitrilo) tetraacetic acid; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; FRET: Förster resonance energy transfer; GDP: guanine dinucleotide phosphate; GEF: guanine nucleotide exchange factor; GFP: green fluorescent protein; GTP: guanine trinucleotide phosphate; GWAS: genome-wide association studies; HEK293: human embryonic kidney 293 cells; HRP: horseradish peroxidase; IBD: inflammatory bowel disease; IgG: immunoglobin G; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; IRGM: immunity related GTPase M; ITGAM/CD11b: integrin subunit alpha M; KO: knockout; LRRK2: leucine rich repeat kinase 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; MPO: myeloperoxidase; NaCl: sodium chloride; NEU: neutrophil; NOD2: nucleotide binding oligomerization domain containing 2; NP40: nonidet-P40; NRBF2: nuclear receptor binding factor 2; PBS: phosphate buffer saline; PCR: polymerase chain reaction; PE: P-phycoerythrin; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3P: phosphatidylinositol-3-phosphate; PTPRC/CD45: protein tyrosine phosphatase receptor type C; SDS-PAGE: sodium dodecylsulphate-polyacrylamide gel electrophoresis; TBST: tris-buffered saline Tween-20; Tris-HCl: trihydroxymethyl aminomethane hydrochloride; TUNEL: TdT-mediated dUTP nick-end labeling; UC: ulcerative colitis; ULK1: unc-51 like autophagy activating kinase 1; WB: western blotting; WT: wild type; YFP: yellow fluorescent protein.
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Affiliation(s)
- Ming-Yue Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Le Liu
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Er-Jin Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Hai-Tao Xiao
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- School of Pharmacy, Shenzhen University, Shenzhen, Guangdong, China
| | - Cui-Zan Cai
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Jing Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Huanxing Su
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Yitao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Jieqiong Tan
- Center for Medical Genetics, School of Life Science, Central South University, Changsha, Hunan, China
| | - Zhuohua Zhang
- Institute of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Juan Wang
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Maojing Yao
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - De-Fang Ouyang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Zhenyu Yue
- Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Min Li
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Ye Chen
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhao-Xiang Bian
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Jia-Hong Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
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Huang HI, Jewell ML, Youssef N, Huang MN, Hauser ER, Fee BE, Rudemiller NP, Privratsky JR, Zhang JJ, Reyes EY, Wang D, Taylor GA, Gunn MD, Ko DC, Cook DN, Chandramohan V, Crowley SD, Hammer GE. Th17 Immunity in the Colon Is Controlled by Two Novel Subsets of Colon-Specific Mononuclear Phagocytes. Front Immunol 2021; 12:661290. [PMID: 33995384 PMCID: PMC8113646 DOI: 10.3389/fimmu.2021.661290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/31/2021] [Indexed: 12/23/2022] Open
Abstract
Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14+CD24+ macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14+CD24+ mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.
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Affiliation(s)
- Hsin-I. Huang
- Department of Immunology, Duke University Medical Center, Durham, NC, United States
| | - Mark L. Jewell
- Department of Immunology, Duke University Medical Center, Durham, NC, United States
| | - Nourhan Youssef
- Department of Immunology, Duke University Medical Center, Durham, NC, United States
| | - Min-Nung Huang
- Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC, United States
| | - Elizabeth R. Hauser
- Department of Biostatistics and Bioinformatics, and Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, United States
- Cooperative Studies Program Epidemiology Center, VA Medical Center, Durham, NC, United States
| | - Brian E. Fee
- Geriatric Research, Education, and Clinical Center, VA Health Care Center, Durham, NC, United States
- Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, United States
| | - Nathan P. Rudemiller
- Department of Medicine, Division of Nephrology, Duke University and Durham VA Medical Centers, Durham, NC, United States
| | - Jamie R. Privratsky
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States
| | - Junyi J. Zhang
- Department of Immunology, Duke University Medical Center, Durham, NC, United States
| | - Estefany Y. Reyes
- Department of Immunology, Duke University Medical Center, Durham, NC, United States
| | - Donghai Wang
- Department of Medicine, Division of Rheumatology and Immunology, Duke University Medical Center, Durham, NC, United States
| | - Gregory A. Taylor
- Department of Immunology, Duke University Medical Center, Durham, NC, United States
- Geriatric Research, Education, and Clinical Center, VA Health Care Center, Durham, NC, United States
- Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, United States
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, United States
| | - Michael D. Gunn
- Department of Immunology, Duke University Medical Center, Durham, NC, United States
- Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC, United States
| | - Dennis C. Ko
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, United States
| | - Donald N. Cook
- Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Durham, NC, United States
| | - Vidyalakshmi Chandramohan
- Department of Neurosurgery and Department of Pathology, Duke University Medical Center, Durham, NC, United States
| | - Steven D. Crowley
- Department of Medicine, Division of Nephrology, Duke University and Durham VA Medical Centers, Durham, NC, United States
| | - Gianna Elena Hammer
- Department of Immunology, Duke University Medical Center, Durham, NC, United States
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, United States
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Singanayagam A, Triantafyllou E. Macrophages in Chronic Liver Failure: Diversity, Plasticity and Therapeutic Targeting. Front Immunol 2021; 12:661182. [PMID: 33868313 PMCID: PMC8051585 DOI: 10.3389/fimmu.2021.661182] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/18/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic liver injury results in immune-driven progressive fibrosis, with risk of cirrhosis development and impact on morbidity and mortality. Persistent liver cell damage and death causes immune cell activation and inflammation. Patients with advanced cirrhosis additionally experience pathological bacterial translocation, exposure to microbial products and chronic engagement of the immune system. Bacterial infections have a high incidence in cirrhosis, with spontaneous bacterial peritonitis being the most common, while the subsequent systemic inflammation, organ failure and immune dysregulation increase the mortality risk. Tissue-resident and recruited macrophages play a central part in the development of inflammation and fibrosis progression. In the liver, adipose tissue, peritoneum and intestines, diverse macrophage populations exhibit great phenotypic and functional plasticity determined by their ontogeny, epigenetic programming and local microenvironment. These changes can, at different times, promote or ameliorate disease states and therefore represent potential targets for macrophage-directed therapies. In this review, we discuss the evidence for macrophage phenotypic and functional alterations in tissue compartments during the development and progression of chronic liver failure in different aetiologies and highlight the potential of macrophage modulation as a therapeutic strategy for liver disease.
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Affiliation(s)
- Arjuna Singanayagam
- Infection and Immunity Clinical Academic Group, St. George’s University Hospitals NHS Foundation Trust, London, United Kingdom
| | - Evangelos Triantafyllou
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
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Ji Y, Zhang Y, Shi H, Jiao Z, Wang SH, Wang C. Constructing Dynamic Brain Functional Networks via Hyper-Graph Manifold Regularization for Mild Cognitive Impairment Classification. Front Neurosci 2021; 15:669345. [PMID: 33867931 PMCID: PMC8047143 DOI: 10.3389/fnins.2021.669345] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 03/11/2021] [Indexed: 12/15/2022] Open
Abstract
Brain functional networks (BFNs) constructed via manifold regularization (MR) have emerged as a powerful tool in finding new biomarkers for brain disease diagnosis. However, they only describe the pair-wise relationship between two brain regions, and cannot describe the functional interaction between multiple brain regions, or the high-order relationship, well. To solve this issue, we propose a method to construct dynamic BFNs (DBFNs) via hyper-graph MR (HMR) and employ it to classify mild cognitive impairment (MCI) subjects. First, we construct DBFNs via Pearson's correlation (PC) method and remodel the PC method as an optimization model. Then, we use k-nearest neighbor (KNN) algorithm to construct the hyper-graph and obtain the hyper-graph manifold regularizer based on the hyper-graph. We introduce the hyper-graph manifold regularizer and the L1-norm regularizer into the PC-based optimization model to optimize DBFNs and obtain the final sparse DBFNs (SDBFNs). Finally, we conduct classification experiments to classify MCI subjects from normal subjects to verify the effectiveness of our method. Experimental results show that the proposed method achieves better classification performance compared with other state-of-the-art methods, and the classification accuracy (ACC), the sensitivity (SEN), the specificity (SPE), and the area under the curve (AUC) reach 82.4946 ± 0.2827%, 77.2473 ± 0.5747%, 87.7419 ± 0.2286%, and 0.9021 ± 0.0007, respectively. This method expands the MR method and DBFNs with more biological significance. It can effectively improve the classification performance of DBFNs for MCI, and has certain reference value for the research and auxiliary diagnosis of Alzheimer's disease (AD).
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Affiliation(s)
- Yixin Ji
- School of Microelectronics and Control Engineering, Changzhou University, Changzhou, China
- School of Computer Science and Artificial Intelligence, Changzhou University, Changzhou, China
| | - Yutao Zhang
- School of Microelectronics and Control Engineering, Changzhou University, Changzhou, China
| | - Haifeng Shi
- Department of Radiology, Changzhou Second People’s Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Zhuqing Jiao
- School of Microelectronics and Control Engineering, Changzhou University, Changzhou, China
- School of Computer Science and Artificial Intelligence, Changzhou University, Changzhou, China
| | - Shui-Hua Wang
- School of Informatics, University of Leicester, Leicester, United Kingdom
| | - Chuang Wang
- School of Medicine, Ningbo University, Ningbo, China
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Luzentales-Simpson M, Pang YCF, Zhang A, Sousa JA, Sly LM. Vedolizumab: Potential Mechanisms of Action for Reducing Pathological Inflammation in Inflammatory Bowel Diseases. Front Cell Dev Biol 2021; 9:612830. [PMID: 33614645 PMCID: PMC7887288 DOI: 10.3389/fcell.2021.612830] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/12/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC), and Crohn’s disease (CD), are a group of disorders characterized by chronic, relapsing, and remitting, or progressive inflammation along the gastrointestinal tract. IBD is accompanied by massive infiltration of circulating leukocytes into the intestinal mucosa. Leukocytes such as neutrophils, monocytes, and T-cells are recruited to the affected site, exacerbating inflammation and causing tissue damage. Current treatments used to block inflammation in IBD include aminosalicylates, corticosteroids, immunosuppressants, and biologics. The first successful biologic, which revolutionized IBD treatment, targeted the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα). Infliximab, adalimumab, and other anti-TNF antibodies neutralize TNFα, preventing interactions with its receptors and reducing the inflammatory response. However, up to 40% of people with IBD become unresponsive to anti-TNFα therapy. Thus, more recent biologics have been designed to block leukocyte trafficking to the inflamed intestine by targeting integrins and adhesins. For example, natalizumab targets the α4 chain of integrin heterodimers, α4β1 and α4β7, on leukocytes. However, binding of α4β1 is associated with increased risk for developing progressive multifocal leukoencephalopathy, an often-fatal disease, and thus, it is not used to treat IBD. To target leukocyte infiltration without this life-threatening complication, vedolizumab was developed. Vedolizumab specifically targets the α4β7 integrin and was approved to treat IBD based on the presumption that it would block T-cell recruitment to the intestine. Though vedolizumab is an effective treatment for IBD, some studies suggest that it may not block T-cell recruitment to the intestine and its mechanism(s) of action remain unclear. Vedolizumab may reduce inflammation by blocking recruitment of T-cells, or pro-inflammatory monocytes and dendritic cells to the intestine, and/or vedolizumab may lead to changes in the programming of innate and acquired immune cells dampening down inflammation.
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Affiliation(s)
- Matthew Luzentales-Simpson
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
| | - Yvonne C F Pang
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
| | - Ada Zhang
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
| | - James A Sousa
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
| | - Laura M Sly
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
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