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1
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Mouttoulingam N, Taleb S. Exploring tryptophan metabolism in cardiometabolic diseases. Trends Endocrinol Metab 2024:S1043-2760(24)00317-5. [PMID: 39694729 DOI: 10.1016/j.tem.2024.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/18/2024] [Accepted: 11/25/2024] [Indexed: 12/20/2024]
Abstract
Tryptophan (Trp) metabolism is linked to health and disease, with indoleamine 2,3-dioxygenase 1 (IDO) being a key enzyme in its breakdown outside the liver. This process produces metabolites that influence metabolic and inflammatory responses. A distinctive feature of the gut is its involvement in three major Trp catabolic pathways: the IDO-driven kynurenine pathway, bacteria-produced indoles, and serotonin. Dysregulation of these pathways is associated with gastrointestinal and chronic inflammatory diseases. Understanding these mechanisms could reveal how gut function affects overall systemic health and disease susceptibility. Here, we review current insights into Trp metabolism, its impact on host physiology and cardiometabolic diseases, and its role in the gut-periphery connection, highlighting its relevance for therapeutic innovation.
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Affiliation(s)
| | - Soraya Taleb
- Université Paris Cité, Inserm, PARCC, F-75015 Paris, France.
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2
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Kang JW, Vemuganti V, Kuehn JF, Ulland TK, Rey FE, Bendlin BB. Gut microbial metabolism in Alzheimer's disease and related dementias. Neurotherapeutics 2024; 21:e00470. [PMID: 39462700 PMCID: PMC11585892 DOI: 10.1016/j.neurot.2024.e00470] [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: 07/29/2024] [Revised: 09/30/2024] [Accepted: 10/04/2024] [Indexed: 10/29/2024] Open
Abstract
Multiple studies over the last decade have established that Alzheimer's disease and related dementias (ADRD) are associated with changes in the gut microbiome. These alterations in organismal composition result in changes in the abundances of functions encoded by the microbial community, including metabolic capabilities, which likely impact host disease mechanisms. Gut microbes access dietary components and other molecules made by the host and produce metabolites that can enter circulation and cross the blood-brain barrier (BBB). In recent years, several microbial metabolites have been associated with or have been shown to influence host pathways relevant to ADRD pathology. These include short chain fatty acids, secondary bile acids, tryptophan derivatives (such as kynurenine, serotonin, tryptamine, and indoles), and trimethylamine/trimethylamine N-oxide. Notably, some of these metabolites cross the BBB and can have various effects on the brain, including modulating the release of neurotransmitters and neuronal function, inducing oxidative stress and inflammation, and impacting synaptic function. Microbial metabolites can also impact the central nervous system through immune, enteroendocrine, and enteric nervous system pathways, these perturbations in turn impact the gut barrier function and peripheral immune responses, as well as the BBB integrity, neuronal homeostasis and neurogenesis, and glial cell maturation and activation. This review examines the evidence supporting the notion that ADRD is influenced by gut microbiota and its metabolites. The potential therapeutic advantages of microbial metabolites for preventing and treating ADRD are also discussed, highlighting their potential role in developing new treatments.
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Affiliation(s)
- Jea Woo Kang
- Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Vaibhav Vemuganti
- Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA
| | - Jessamine F Kuehn
- Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA
| | - Tyler K Ulland
- Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Federico E Rey
- Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA
| | - Barbara B Bendlin
- Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
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3
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Chajadine M, Laurans L, Radecke T, Mouttoulingam N, Al-Rifai R, Bacquer E, Delaroque C, Rytter H, Bredon M, Knosp C, Vilar J, Fontaine C, Suffee N, Vandestienne M, Esposito B, Dairou J, Launay JM, Callebert J, Tedgui A, Ait-Oufella H, Sokol H, Chassaing B, Taleb S. Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice. Nat Commun 2024; 15:6390. [PMID: 39080345 PMCID: PMC11289133 DOI: 10.1038/s41467-024-50807-x] [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: 08/04/2023] [Accepted: 07/22/2024] [Indexed: 08/02/2024] Open
Abstract
Tryptophan (Trp) is an essential amino acid, whose metabolism is a key gatekeeper of intestinal homeostasis. Yet, its systemic effects, particularly on atherosclerosis, remain unknown. Here we show that high-fat diet (HFD) increases the activity of intestinal indoleamine 2, 3-dioxygenase 1 (IDO), which shifts Trp metabolism from the production of microbiota-derived indole metabolites towards kynurenine production. Under HFD, the specific deletion of IDO in intestinal epithelial cells leads to intestinal inflammation, impaired intestinal barrier, augmented lesional T lymphocytes and atherosclerosis. This is associated with an increase in serotonin production and a decrease in indole metabolites, thus hijacking Trp for the serotonin pathway. Inhibition of intestinal serotonin production or supplementation with indole derivatives alleviates plaque inflammation and atherosclerosis. In summary, we uncover a pivotal role of intestinal IDO in the fine-tuning of Trp metabolism with systemic effects on atherosclerosis, paving the way for new therapeutic strategies to relieve gut-associated inflammatory diseases.
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Affiliation(s)
- Mouna Chajadine
- Université Paris Cité, Inserm, PARCC, F-75015, Paris, France
| | | | - Tobias Radecke
- Université Paris Cité, Inserm, PARCC, F-75015, Paris, France
| | | | - Rida Al-Rifai
- Université Paris Cité, Inserm, PARCC, F-75015, Paris, France
| | - Emilie Bacquer
- Université Paris Cité, Inserm, PARCC, F-75015, Paris, France
| | - Clara Delaroque
- Microbiome-Host interactions, Institut Pasteur, Université Paris Cité, INSERM U1306, Paris, France
- INSERM U1016, Team "Mucosal microbiota in chronic inflammatory diseases", CNRS UMR10 8104, Université Paris Cité, Paris, France
| | - Héloïse Rytter
- Microbiome-Host interactions, Institut Pasteur, Université Paris Cité, INSERM U1306, Paris, France
- INSERM U1016, Team "Mucosal microbiota in chronic inflammatory diseases", CNRS UMR10 8104, Université Paris Cité, Paris, France
| | - Marius Bredon
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012, Paris, France
- Paris Centre for Microbiome Medicine (PaCeMM) FHU, Paris, France
| | - Camille Knosp
- Université Paris Cité, Inserm, PARCC, F-75015, Paris, France
| | - José Vilar
- Université Paris Cité, Inserm, PARCC, F-75015, Paris, France
| | - Coralie Fontaine
- Inserm U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, cedex, France
| | - Nadine Suffee
- Université Paris Cité, Inserm, PARCC, F-75015, Paris, France
| | | | - Bruno Esposito
- Université Paris Cité, Inserm, PARCC, F-75015, Paris, France
| | - Julien Dairou
- Université Paris cité, CNRS, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, F-75006 Paris, France. 45 rue des Saints Pères, 75006, Paris, France
| | - Jean Marie Launay
- Assistance Publique Hôpitaux de Paris, Service de Biochimie and INSERM U942, Hôpital Lariboisière, Paris, France
| | - Jacques Callebert
- Assistance Publique Hôpitaux de Paris, Service de Biochimie and INSERM U942, Hôpital Lariboisière, Paris, France
| | - Alain Tedgui
- Université Paris Cité, Inserm, PARCC, F-75015, Paris, France
| | | | - Harry Sokol
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012, Paris, France
- Paris Centre for Microbiome Medicine (PaCeMM) FHU, Paris, France
- Université Paris-Saclay, INRAe, AgroParisTech, Micalis institute, Jouy-en-Josas, France Université Paris-Saclay, INRAe, AgroParisTech, Micalis institute, Jouy-en-Josas, France
| | - Benoit Chassaing
- Microbiome-Host interactions, Institut Pasteur, Université Paris Cité, INSERM U1306, Paris, France
- INSERM U1016, Team "Mucosal microbiota in chronic inflammatory diseases", CNRS UMR10 8104, Université Paris Cité, Paris, France
| | - Soraya Taleb
- Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.
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4
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Shang Z, Ma Z, Wu E, Chen X, Tuo B, Li T, Liu X. Effect of metabolic reprogramming on the immune microenvironment in gastric cancer. Biomed Pharmacother 2024; 170:116030. [PMID: 38128177 DOI: 10.1016/j.biopha.2023.116030] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/03/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
Gastric cancer (GC) is a malignant tumor of the gastrointestinal tract with a high mortality rate worldwide, a low early detection rate and a poor prognosis. The rise of metabolomics has facilitated the early detection and treatment of GC. Metabolism in the GC tumor microenvironment (TME) mainly includes glucose metabolism, lipid metabolism and amino acid metabolism, which provide energy and nutrients for GC cell proliferation and migration. Abnormal tumor metabolism can influence tumor progression by regulating the functions of immune cells and immune molecules in the TME, thereby contributing to tumor immune escape. Thus, in this review, we summarize the impact of metabolism on the TME during GC progression. We also propose novel strategies to modulate antitumor immune responses by targeting metabolism.
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Affiliation(s)
- Zhengye Shang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Enqin Wu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Xingzhao Chen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Taolang Li
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Dalian Road 149, Zunyi 563000, China.
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China.
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Charkoftaki G, Aalizadeh R, Santos-Neto A, Tan WY, Davidson EA, Nikolopoulou V, Wang Y, Thompson B, Furnary T, Chen Y, Wunder EA, Coppi A, Schulz W, Iwasaki A, Pierce RW, Cruz CSD, Desir GV, Kaminski N, Farhadian S, Veselkov K, Datta R, Campbell M, Thomaidis NS, Ko AI, Thompson DC, Vasiliou V. An AI-powered patient triage platform for future viral outbreaks using COVID-19 as a disease model. Hum Genomics 2023; 17:80. [PMID: 37641126 PMCID: PMC10463861 DOI: 10.1186/s40246-023-00521-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 07/30/2023] [Indexed: 08/31/2023] Open
Abstract
Over the last century, outbreaks and pandemics have occurred with disturbing regularity, necessitating advance preparation and large-scale, coordinated response. Here, we developed a machine learning predictive model of disease severity and length of hospitalization for COVID-19, which can be utilized as a platform for future unknown viral outbreaks. We combined untargeted metabolomics on plasma data obtained from COVID-19 patients (n = 111) during hospitalization and healthy controls (n = 342), clinical and comorbidity data (n = 508) to build this patient triage platform, which consists of three parts: (i) the clinical decision tree, which amongst other biomarkers showed that patients with increased eosinophils have worse disease prognosis and can serve as a new potential biomarker with high accuracy (AUC = 0.974), (ii) the estimation of patient hospitalization length with ± 5 days error (R2 = 0.9765) and (iii) the prediction of the disease severity and the need of patient transfer to the intensive care unit. We report a significant decrease in serotonin levels in patients who needed positive airway pressure oxygen and/or were intubated. Furthermore, 5-hydroxy tryptophan, allantoin, and glucuronic acid metabolites were increased in COVID-19 patients and collectively they can serve as biomarkers to predict disease progression. The ability to quickly identify which patients will develop life-threatening illness would allow the efficient allocation of medical resources and implementation of the most effective medical interventions. We would advocate that the same approach could be utilized in future viral outbreaks to help hospitals triage patients more effectively and improve patient outcomes while optimizing healthcare resources.
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Affiliation(s)
- Georgia Charkoftaki
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
| | - Reza Aalizadeh
- Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Zografou, 15771, Greece
| | - Alvaro Santos-Neto
- São Carlos Institute of Chemistry, University of São Paulo, São Carlos, SP, 13566-590, Brazil
| | - Wan Ying Tan
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
- Internal Medicine Residency Program, Department of Internal Medicine, Norwalk Hospital, Norwalk, CT, USA
| | - Emily A Davidson
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
| | - Varvara Nikolopoulou
- Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Zografou, 15771, Greece
| | - Yewei Wang
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
| | - Brian Thompson
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
| | - Tristan Furnary
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
- Harvard Medical School, Harvard University, Boston, MA, USA
| | - Ying Chen
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
| | - Elsio A Wunder
- Department of Epidemiology of Microbial Diseases, Yale School of Public Health, Yale University, New Haven, CT, USA
- Institute Gonçalo Moniz, Fundação Oswaldo Cruz, Brazilian Ministry of Health, Salvador, Brazil
| | - Andreas Coppi
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, USA
| | - Wade Schulz
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, USA
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Akiko Iwasaki
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
- Howard Hughes Medical Institute, MD, Chevy Chase, USA
| | - Richard W Pierce
- Department of Pediatrics , Yale School of Medicine, New Haven, CT, USA
| | - Charles S Dela Cruz
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Gary V Desir
- Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT, USA
| | - Naftali Kaminski
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Shelli Farhadian
- Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
- Department of Epidemiology of Microbial Diseases, Yale School of Public Health, Yale University, New Haven, USA
| | - Kirill Veselkov
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
- Department of Surgery and Cancer, Imperial College London, South Kensington Campus, London, UK
| | - Rupak Datta
- Veterans Affairs Connecticut Healthcare System, CT, West Haven, USA
- Department of Internal Medicine, Yale School of Medicine, CT, New Haven, USA
| | - Melissa Campbell
- Department of Pediatrics, Division of Pediatric Infectious Diseases, School of Medicine, Duke University, NC, Durham, USA
| | - Nikolaos S Thomaidis
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
- Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Zografou, 15771, Greece
| | - Albert I Ko
- Department of Epidemiology of Microbial Diseases, Yale School of Public Health, Yale University, New Haven, CT, USA
- Institute Gonçalo Moniz, Fundação Oswaldo Cruz, Brazilian Ministry of Health, Salvador, Brazil
- Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
| | - David C Thompson
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.
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Ang HP, Makpol S, Nasaruddin ML, Ahmad NS, Tan JK, Wan Zaidi WA, Embong H. Lipopolysaccharide-Induced Delirium-like Behaviour in a Rat Model of Chronic Cerebral Hypoperfusion Is Associated with Increased Indoleamine 2,3-Dioxygenase Expression and Endotoxin Tolerance. Int J Mol Sci 2023; 24:12248. [PMID: 37569622 PMCID: PMC10418785 DOI: 10.3390/ijms241512248] [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: 06/15/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 08/13/2023] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO) and the tryptophan-kynurenine pathway (TRP-KP) are upregulated in ageing and could be implicated in the pathogenesis of delirium. This study evaluated the role of IDO/KP in lipopolysaccharide (LPS)-induced delirium in an animal model of chronic cerebral hypoperfusion (CCH), a proposed model for delirium. CCH was induced by a permanent bilateral common carotid artery ligation (BCCAL) in Sprague Dawley rats to trigger chronic neuroinflammation-induced neurodegeneration. Eight weeks after permanent BCCAL, the rats were treated with a single systemic LPS. The rats were divided into three groups: (1) post-BCCAL rats treated with intraperitoneal (i.p.) saline, (2) post-BCCAL rats treated with i.p. LPS 100 μg/kg, and (3) sham-operated rats treated with i.p. LPS 100 μg/kg. Each group consisted of 10 male rats. To elucidate the LPS-induced delirium-like behaviour, natural and learned behaviour changes were assessed by a buried food test (BFT), open field test (OFT), and Y-maze test at 0, 24-, 48-, and 72 h after LPS treatment. Serum was collected after each session of behavioural assessment. The rats were euthanised after the last serum collection, and the hippocampi and cerebral cortex were collected. The TRP-KP neuroactive metabolites were measured in both serum and brain tissues using ELISA. Our data show that LPS treatment in CCH rats was associated with acute, transient, and fluctuated deficits in natural and learned behaviour, consistent with features of delirium. These behaviour deficits were mild compared to the sham-operated rats, which exhibited robust behaviour impairments. Additionally, heightened hippocampal IDO expression in the LPS-treated CCH rats was associated with reduced serum KP activity together with a decrease in the hippocampal quinolinic acid (QA) expression compared to the sham-operated rats, suggested for the presence of endotoxin tolerance through the immunomodulatory activity of IDO in the brain. These data provide new insight into the underlying mechanisms of delirium, and future studies should further explore the role of IDO modulation and its therapeutic potential in delirium.
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Affiliation(s)
- Hui Phing Ang
- Department of Emergency Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia (N.S.A.)
| | - Suzana Makpol
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (M.L.N.); (J.K.T.)
| | - Muhammad Luqman Nasaruddin
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (M.L.N.); (J.K.T.)
| | - Nurul Saadah Ahmad
- Department of Emergency Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia (N.S.A.)
| | - Jen Kit Tan
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (M.L.N.); (J.K.T.)
| | - Wan Asyraf Wan Zaidi
- Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia;
| | - Hashim Embong
- Department of Emergency Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia (N.S.A.)
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7
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Wu HW, Chen HD, Chen YH, Mao XL, Feng YY, Li SW, Zhou XB. The Effects of Programmed Cell Death of Mesenchymal Stem Cells on the Development of Liver Fibrosis. Stem Cells Int 2023; 2023:4586398. [PMID: 37214784 PMCID: PMC10195177 DOI: 10.1155/2023/4586398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 02/06/2023] [Accepted: 04/02/2023] [Indexed: 05/24/2023] Open
Abstract
Mesenchymal stem cells have shown noticeable potential for unlimited self-renewal. They can differentiate into specific somatic cells, integrate into target tissues via cell-cell contact, paracrine effects, exosomes, and other processes and then regulate the target cells and tissues. Studies have demonstrated that transplantation of MSCs could decrease the expression and concentration of collagen in the liver, thereby reducing liver fibrosis. A growing body of evidence indicates that apoptotic MSCs could inhibit harmful immune responses and reduce inflammatory responses more effectively than viable MSCs. Accumulating evidence suggests that mitochondrial transfer from MSCs is a novel strategy for the regeneration of various damaged cells via the rescue of their respiratory activities. This study is aimed at reviewing the functions of MSCs and the related roles of the programmed cell death of MSCs, including autophagy, apoptosis, pyroptosis, and ferroptosis, as well as the regulatory pathogenic mechanisms of MSCs in liver fibrosis. Research has demonstrated that the miR-200B-3p gene is differentially expressed gene between LF and normal liver samples, and that the miR-200B-3p gene expression is positively correlated with the degree of liver fibrosis, suggesting that MSCs could inhibit liver fibrosis through pyroptosis. It was confirmed that circulating monocytes could deliver MSC-derived immunomodulatory molecules to different sites by phagocytosis of apoptotic MSCs, thereby achieving systemic immunosuppression. Accordingly, it was suggested that characterization of the programmed cell death-mediated immunomodulatory signaling pathways in MSCs should be a focus of research.
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Affiliation(s)
- Hong-wei Wu
- Department of Infectious Diseases, Taizhou Enze Medical Center (Group) Enze Hospital, Taizhou, Zhejiang, China
| | - He-dan Chen
- Department of Infectious Diseases, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Ya-hong Chen
- Health Management Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Xin-li Mao
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yu-yi Feng
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shao-wei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Xian-bin Zhou
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
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8
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Linking nervous and immune systems in psychiatric illness: A meta-analysis of the kynurenine pathway. Brain Res 2023; 1800:148190. [PMID: 36463958 DOI: 10.1016/j.brainres.2022.148190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/13/2022] [Accepted: 11/26/2022] [Indexed: 12/03/2022]
Abstract
Tryptophan is an essential amino acid absorbed by the gut depending on a homoeostatic microbiome. Up to 95% of unbound tryptophan is converted into tryptophan catabolites (TRYCATs) through the kynurenine system. Recent studies identified conflicting associations between altered levels of TRYCATs and genetic polymorphisms in major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD). This meta-analysis aimed to understand how tryptophan catabolic pathways are altered in MDD, SCZ, and BD. When compared to healthy controls, participants with MDD had moderately lower levels of tryptophan associated with a moderate increase of kynurenine/tryptophan ratios and no differences in kynurenine. While significant differences were found in SCZ for any of the TRYCATs, studies on kynurenic acid found opposing directions of effect sizes depending on the sample source. Unique changes in levels of TRYCATs were also observed in BD. Dynamic changes in levels of cytokines and other immune/inflammatory elements modulate the transcription and activity of kynurenine system enzymes, which lastly seems to be impacting glutamatergic neurotransmission via N-methyl-D-aspartate and α-7 nicotine receptors.
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9
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Riaz B, Islam SMS, Ryu HM, Sohn S. CD83 Regulates the Immune Responses in Inflammatory Disorders. Int J Mol Sci 2023; 24:ijms24032831. [PMID: 36769151 PMCID: PMC9917562 DOI: 10.3390/ijms24032831] [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: 12/22/2022] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Activating the immune system plays an important role in maintaining physiological homeostasis and defending the body against harmful infections. However, abnormalities in the immune response can lead to various immunopathological responses and severe inflammation. The activation of dendritic cells (DCs) can influence immunological responses by promoting the differentiation of T cells into various functional subtypes crucial for the eradication of pathogens. CD83 is a molecule known to be expressed on mature DCs, activated B cells, and T cells. Two isotypes of CD83, a membrane-bound form and a soluble form, are subjects of extensive scientific research. It has been suggested that CD83 is not only a ubiquitous co-stimulatory molecule but also a crucial player in monitoring and resolving inflammatory reactions. Although CD83 has been involved in immunological responses, its functions in autoimmune diseases and effects on pathogen immune evasion remain unclear. Herein, we outline current immunological findings and the proposed function of CD83 in inflammatory disorders.
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Affiliation(s)
- Bushra Riaz
- Department of Biomedical Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - S. M. Shamsul Islam
- Department of Microbiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Hye Myung Ryu
- Department of Biomedical Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Seonghyang Sohn
- Department of Biomedical Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea
- Department of Microbiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
- Correspondence:
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10
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Műzes G, Bohusné Barta B, Szabó O, Horgas V, Sipos F. Cell-Free DNA in the Pathogenesis and Therapy of Non-Infectious Inflammations and Tumors. Biomedicines 2022; 10:biomedicines10112853. [PMID: 36359370 PMCID: PMC9687442 DOI: 10.3390/biomedicines10112853] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 10/31/2022] [Accepted: 11/07/2022] [Indexed: 11/09/2022] Open
Abstract
The basic function of the immune system is the protection of the host against infections, along with the preservation of the individual antigenic identity. The process of self-tolerance covers the discrimination between self and foreign antigens, including proteins, nucleic acids, and larger molecules. Consequently, a broken immunological self-tolerance results in the development of autoimmune or autoinflammatory disorders. Immunocompetent cells express pattern-recognition receptors on their cell membrane and cytoplasm. The majority of endogenous DNA is located intracellularly within nuclei and mitochondria. However, extracellular, cell-free DNA (cfDNA) can also be detected in a variety of diseases, such as autoimmune disorders and malignancies, which has sparked interest in using cfDNA as a possible biomarker. In recent years, the widespread use of liquid biopsies and the increasing demand for screening, as well as monitoring disease activity and therapy response, have enabled the revival of cfDNA research. The majority of studies have mainly focused on the function of cfDNA as a biomarker. However, research regarding the immunological consequences of cfDNA, such as its potential immunomodulatory or therapeutic benefits, is still in its infancy. This article discusses the involvement of various DNA-sensing receptors (e.g., absent in melanoma-2; Toll-like receptor 9; cyclic GMP-AMP synthase/activator of interferon genes) in identifying host cfDNA as a potent danger-associated molecular pattern. Furthermore, we aim to summarize the results of the experimental studies that we recently performed and highlight the immunomodulatory capacity of cfDNA, and thus, the potential for possible therapeutic consideration.
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Affiliation(s)
| | | | | | | | - Ferenc Sipos
- Correspondence: ; Tel.: +36-20-478-0752; Fax: +36-1-266-0816
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Chen S, Jiang J, Shen A, Miao Y, Cao Y, Zhang Y, Cong P, Gao P. Rewired Metabolism of Amino Acids and Its Roles in Glioma Pathology. Metabolites 2022; 12:918. [PMID: 36295820 PMCID: PMC9611130 DOI: 10.3390/metabo12100918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 09/24/2022] [Accepted: 09/26/2022] [Indexed: 11/21/2022] Open
Abstract
Amino acids (AAs) are indispensable building blocks of diverse bio-macromolecules as well as functional regulators for various metabolic processes. The fact that cancer cells live with a voracious appetite for specific AAs has been widely recognized. Glioma is one of the most lethal malignancies occurring in the central nervous system. The reprogrammed metabolism of AAs benefits glioma proliferation, signal transduction, epigenetic modification, and stress tolerance. Metabolic alteration of specific AAs also contributes to glioma immune escape and chemoresistance. For clinical consideration, fluctuations in the concentrations of AAs observed in specific body fluids provides opportunities to develop new diagnosis and prognosis markers. This review aimed at providing an extra dimension to understanding glioma pathology with respect to the rewired AA metabolism. A deep insight into the relevant fields will help to pave a new way for new therapeutic target identification and valuable biomarker development.
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Affiliation(s)
- Sirui Chen
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, China
| | - Jingjing Jiang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Ao Shen
- HE University, Shenyang 110163, China
| | - Ying Miao
- E&M College, Shenyang Aerospace University, Shenyang 110136, China
| | - Yunfeng Cao
- Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China
| | - Ying Zhang
- Internal Medicine Department, Dalian Public Health Clinical Center, Dalian 116033, China
| | - Peiyu Cong
- Neurosurgery Department, Affiliated Dalian Municipal Central Hospital of Dalian Medical University, Dalian 116022, China
| | - Peng Gao
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, China
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12
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Lingua Plicata Associated with Increased Level of Proinflammatory Cytokines in Gingival Cervical Fluid: Possible New Sign in Ulcerative Colitis. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2022. [DOI: 10.2478/sjecr-2021-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
Ulcerative colitis (UC) is a complex disease in which the interaction of genetic, environmental, and microbial factors drives chronic intestinal inflammation. Gastrointestinal symptoms are predominant including pathological manifestations in the oral cavity, as well as extra-intestinal complications.
Lingua plicata (LP) is a condition characterized by an increased number of fissures and grooves at the central and lateral aspects of the dorsal surface of the tongue. LP is usually asymptomatic and discovered incidentally, but the accumulation of food in the fissures and grooves can lead to focal glossitis and halitosis.
In this study, we analyzed the level of proinflammatory cytokines in gingival crevicular fluid (GCF) and demonstrated that proinflammatory cytokines IFN-γ, IL-12, and IL-1β were significantly increased in the group of UC patients when compared with healthy controls. Obtained results have shown that 35% of UC patients have lingua plicata. The GCF levels of IFN-γ and IL-12 were higher in UC patients with LP compared with UC patients without lingua plicata.
In conclusion, increased GCF values of IFN-γ and IL-12, in UC patients with LP may be considered as a sign of the disease progression and, consequently, of a poor prognosis for patients.
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Brice DP, Murray GI, Wilson HM, Porter RJ, Berry S, Durum SK, McLean MH. Interleukin-27 Regulates the Function of the Gastrointestinal Epithelial Barrier in a Human Tissue-Derived Organoid Model. BIOLOGY 2022; 11:biology11030427. [PMID: 35336801 PMCID: PMC8945023 DOI: 10.3390/biology11030427] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/28/2022] [Accepted: 03/04/2022] [Indexed: 11/25/2022]
Abstract
A treatment with direct healing effects on the gastrointestinal epithelial barrier is desirable for inflammatory bowel disease (IBD). Interleukin-27 (IL-27) is an immunoregulatory cytokine, and oral delivery is an effective treatment in murine models of IBD. We aimed to define IL-27 effects on the human gastrointestinal epithelial barrier. We characterised gene and protein expression of permeability mediators in a human colon-derived organoid model. Functional permeability was determined in an organoid-derived 2D monolayer by transepithelial electrical resistance. IL-27 effects on epithelial innate immune responses were assessed through expression of cytokines, anti-microbial peptides and MUC genes. IL-27 effects on wound healing and proliferation were determined in human colon epithelial cell lines. IL-27 led to restoration of permeability regulation following inflammatory cytokine insult (p = 0.001), associated with differential expression of tight junction mediators with decrease in claudin 2 (p = 0.024) and increase in claudin 4 (p < 0.001), E-cadherin (p < 0.001) and zona occludens (p = 0.0014). IL-27 evoked differential gene expression of epithelial-derived innate immune responses (reduced IL1B and IL18, and increased IL33, HBD1, MUC1 and MUC2; p < 0.012). IL-27 induced epithelial barrier wound healing through restitution (p < 0.001), and increased proliferation (p < 0.001) following injury. Overall, IL-27 provokes mucosal healing of the human gastrointestinal epithelial barrier.
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Affiliation(s)
- Daniel P. Brice
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (D.P.B.); (G.I.M.); (H.M.W.); (S.B.)
| | - Graeme I. Murray
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (D.P.B.); (G.I.M.); (H.M.W.); (S.B.)
| | - Heather M. Wilson
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (D.P.B.); (G.I.M.); (H.M.W.); (S.B.)
| | - Ross J. Porter
- Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Susan Berry
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (D.P.B.); (G.I.M.); (H.M.W.); (S.B.)
| | - Scott K. Durum
- Cytokines and Immunity Section, Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), National Institute of Health (NIH), Frederick, MD 21702, USA;
| | - Mairi H. McLean
- Division of Molecular & Clinical Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UK
- Correspondence:
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Markandey M, Bajaj A, Ilott NE, Kedia S, Travis S, Powrie F, Ahuja V. Gut microbiota: sculptors of the intestinal stem cell niche in health and inflammatory bowel disease. Gut Microbes 2022; 13:1990827. [PMID: 34747326 PMCID: PMC8583176 DOI: 10.1080/19490976.2021.1990827] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Intestinal epithelium represents a dynamic and diverse cellular system that continuously interacts with gut commensals and external cues. Intestinal stem cells, which lie at the heart of epithelial renewal and turnover, proliferate to maintain a steady stem cell population and differentiate to form functional epithelial cell types. This rather sophisticated assembly-line is maintained by an elaborate micro-environment, sculpted by a myriad of host and gut microbiota-derived signals, forming an intestinal stem cell niche. This complex, yet crucial signaling niche undergoes dynamic changes during homeostasis and chronic intestinal inflammation. Inflammatory bowel disease refers to a chronic inflammatory response toward pathogenic or commensal microbiota, in a genetically susceptible host. Compositional and functional alterations in gut microbiota are pathognomonic of IBD.The present review highlights the modulatory role of gut microbiota on the intestinal stem cell niche during homeostasis and inflammatory bowel disease. We discuss the mechanisms of direct action of gut commensals (through microbiota-derived or microbiota-influenced metabolites) on ISCs, followed by their effects via other epithelial and immune cell types.
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Affiliation(s)
- Manasvini Markandey
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Aditya Bajaj
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Simon Travis
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Fiona Powrie
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India,CONTACT Vineet Ahuja Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India, 110029
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15
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Cutuli D, Giacovazzo G, Decandia D, Coccurello R. Alzheimer's disease and depression in the elderly: A trajectory linking gut microbiota and serotonin signaling. Front Psychiatry 2022; 13:1010169. [PMID: 36532180 PMCID: PMC9750201 DOI: 10.3389/fpsyt.2022.1010169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/28/2022] [Indexed: 12/05/2022] Open
Abstract
The occurrence of neuropsychiatric symptoms in the elderly is viewed as an early sign of subsequent cognitive deterioration and conversion from mild cognitive impairment to Alzheimer's disease. The prognosis in terms of both the severity and progression of clinical dementia is generally aggravated by the comorbidity of neuropsychiatric symptoms and decline in cognitive function. Undeniably, aging and in particular unhealthy aging, is a silent "engine of neuropathology" over which multiple changes take place, including drastic alterations of the gut microbial ecosystem. This narrative review evaluates the role of gut microbiota changes as a possible unifying concept through which the comorbidity of neuropsychiatric symptoms and Alzheimer's disease can be considered. However, since the heterogeneity of neuropsychiatric symptoms, it is improbable to describe the same type of alterations in the bacteria population observed in patients with Alzheimer's disease, as well as it is improbable that the variety of drugs used to treat neuropsychiatric symptoms might produce changes in gut bacterial diversity similar to that observed in the pathophysiology of Alzheimer's disease. Depression seems to be another very intriguing exception, as it is one of the most frequent neuropsychiatric symptoms in dementia and a mood disorder frequently associated with brain aging. Antidepressants (i.e., serotonin reuptake inhibitors) or tryptophan dietary supplementation have been shown to reduce Amyloid β-loading, reinstate microbial diversity and reduce the abundance of bacterial taxa dominant in depression and Alzheimer's disease. This review briefly examines this trajectory by discussing the dysfunction of gut microbiota composition, selected bacterial taxa, and alteration of tryptophan and serotonin metabolism/neurotransmission as overlapping in-common mechanisms involved with depression, Alzheimer's disease, and unhealthy aging.
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Affiliation(s)
- Debora Cutuli
- Department of Psychology, University of Rome La Sapienza, Rome, Italy.,European Center for Brain Research, Santa Lucia Foundation IRCCS, Rome, Italy
| | - Giacomo Giacovazzo
- European Center for Brain Research, Santa Lucia Foundation IRCCS, Rome, Italy
| | - Davide Decandia
- Department of Psychology, University of Rome La Sapienza, Rome, Italy.,European Center for Brain Research, Santa Lucia Foundation IRCCS, Rome, Italy
| | - Roberto Coccurello
- European Center for Brain Research, Santa Lucia Foundation IRCCS, Rome, Italy.,Institute for Complex Systems (ISC), National Council of Research (CNR), Rome, Italy
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16
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Wee HN, Liu JJ, Ching J, Kovalik JP, Lim SC. The Kynurenine Pathway in Acute Kidney Injury and Chronic Kidney Disease. Am J Nephrol 2021; 52:771-787. [PMID: 34753140 PMCID: PMC8743908 DOI: 10.1159/000519811] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND The kynurenine pathway (KP) is the major catabolic pathway for tryptophan degradation. The KP plays an important role as the sole de novo nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in normal human physiology and functions as a counter-regulatory mechanism to mitigate immune responses during inflammation. Although the KP has been implicated in a variety of disorders including Huntington's disease, seizures, cardiovascular disease, and osteoporosis, its role in renal diseases is seldom discussed. SUMMARY This review summarizes the roles of the KP and its metabolites in acute kidney injury (AKI) and chronic kidney disease (CKD) based on current literature evidence. Metabolomics studies demonstrated that the KP metabolites were significantly altered in patients and animal models with AKI or CKD. The diagnostic and prognostic values of the KP metabolites in AKI and CKD were highlighted in cross-sectional and longitudinal human observational studies. The biological impact of the KP on the pathophysiology of AKI and CKD has been studied in experimental models of different etiologies. In particular, the activation of the KP was found to confer protection in animal models of glomerulonephritis, and its immunomodulatory mechanism may involve the regulation of T cell subsets such as Th17 and regulatory T cells. Manipulation of the KP to increase NAD+ production or diversion toward specific KP metabolites was also found to be beneficial in animal models of AKI. Key Messages: KP metabolites are reported to be dysregulated in human observational and animal experimental studies of AKI and CKD. In AKI, the magnitude and direction of changes in the KP depend on the etiology of the damage. In CKD, KP metabolites are altered with the onset and progression of CKD all the way to advanced stages of the disease, including uremia and its related vascular complications. The activation of the KP and diversion to specific sub-branches are currently being explored as therapeutic strategies in these diseases, especially with regards to the immunomodulatory effects of certain KP metabolites. Further elucidation of the KP may hold promise for the development of biomarkers and targeted therapies for these kidney diseases.
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Affiliation(s)
| | - Jian-Jun Liu
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore
| | - Jianhong Ching
- Duke-NUS Medical School, Singapore, Singapore
- KK Research Centre, KK Women's and Children's Hospital, Singapore, Singapore
| | | | - Su Chi Lim
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
- Diabetes Centre, Admiralty Medical Centre, Singapore, Singapore
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Wen X, Wang HG, Zhang MN, Zhang MH, Wang H, Yang XZ. Fecal microbiota transplantation ameliorates experimental colitis via gut microbiota and T-cell modulation. World J Gastroenterol 2021; 27:2834-2849. [PMID: 34135557 PMCID: PMC8173381 DOI: 10.3748/wjg.v27.i21.2834] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/30/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Emerging evidence has demonstrated that fecal microbiota transplantation (FMT) has a promising therapeutic effect on mice with experimental colitis and patients with ulcerative colitis (UC), although the mechanism of FMT is unclear.
AIM To evaluate the protective effect of FMT on UC and clarify its potential dependence on the gut microbiota, through association analysis of gut microbiota with colon transcriptome in mice.
METHODS Dextran sodium sulfate (DSS)-induced experimental colitis was established and fecal microbiota was transplanted by gavage. Severity of colon inflammation was measured by body weight, disease activity index, colon length and histological score. Gut microbiota alteration was analyzed through 16S ribosomal ribonucleic acid sequencing. The differentially expressed genes (DEGs) in the colon were obtained by transcriptome sequencing. The activation status of colonic T lymphocytes in the lamina propria was evaluated by flow cytometry.
RESULTS Compared with the DSS group, the weight loss, colon length shortening and inflammation were significantly alleviated in the FMT group. The scores of disease activity index and colon histology decreased obviously after FMT. FMT restored the balance of gut microbiota, especially by upregulating the relative abundance of Lactobacillus and downregulating the relative abundance of Clostridium_sensu_stricto_1 and Turicibacter. In the transcriptomic analysis, 128 DEGs intersected after DSS treatment and FMT. Functional annotation analysis suggested that these DEGs were mainly involved in T-lymphocyte activation. In the DSS group, there was an increase in colonic T helper CD4+ and T cytotoxic CD8+ cells by flow cytometry. FMT selectively downregulated the ratio of colonic CD4+ and CD8+ T cells to maintain intestinal homeostasis. Furthermore, Clostri dium_sensu_stricto_1 was significantly related to inflammation-related genes including REG3G, CCL8 and IDO1.
CONCLUSION FMT ameliorated DSS-induced colitis in mice via regulating the gut microbiota and T-cell modulation.
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Affiliation(s)
- Xin Wen
- Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai'an 223300, Jiangsu Province, China
| | - Hong-Gang Wang
- Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai'an 223300, Jiangsu Province, China
| | - Min-Na Zhang
- Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai'an 223300, Jiangsu Province, China
| | - Meng-Hui Zhang
- Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai'an 223300, Jiangsu Province, China
| | - Han Wang
- Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai'an 223300, Jiangsu Province, China
| | - Xiao-Zhong Yang
- Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai'an 223300, Jiangsu Province, China
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18
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Ouyang Y, Wen L, Armstrong JA, Chvanov M, Latawiec D, Cai W, Awais M, Mukherjee R, Huang W, Gough PJ, Bertin J, Tepikin AV, Sutton R, Criddle DN. Protective Effects of Necrostatin-1 in Acute Pancreatitis: Partial Involvement of Receptor Interacting Protein Kinase 1. Cells 2021; 10:1035. [PMID: 33925729 PMCID: PMC8145347 DOI: 10.3390/cells10051035] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/18/2022] Open
Abstract
Acute pancreatitis (AP) is a severe and potentially fatal disease caused predominantly by alcohol excess and gallstones, which lacks a specific therapy. The role of Receptor-Interacting Protein Kinase 1 (RIPK1), a key component of programmed necrosis (Necroptosis), is unclear in AP. We assessed the effects of RIPK1 inhibitor Necrostatin-1 (Nec-1) and RIPK1 modification (RIPK1K45A: kinase dead) in bile acid (TLCS-AP), alcoholic (FAEE-AP) and caerulein hyperstimulation (CER-AP) mouse models. Involvement of collateral Nec-1 target indoleamine 2,3-dioxygenase (IDO) was probed with the inhibitor Epacadostat (EPA). Effects of Nec-1 and RIPK1K45A were also compared on pancreatic acinar cell (PAC) fate in vitro and underlying mechanisms explored. Nec-1 markedly ameliorated histological and biochemical changes in all models. However, these were only partially reduced or unchanged in RIPK1K45A mice. Inhibition of IDO with EPA was protective in TLCS-AP. Both Nec-1 and RIPK1K45A modification inhibited TLCS- and FAEE-induced PAC necrosis in vitro. Nec-1 did not affect TLCS-induced Ca2+ entry in PACs, however, it inhibited an associated ROS elevation. The results demonstrate protective actions of Nec-1 in multiple models. However, RIPK1-dependent necroptosis only partially contributed to beneficial effects, and actions on targets such as IDO are likely to be important.
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Affiliation(s)
- Yulin Ouyang
- Department of Molecular Physiology & Cell Signalling, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK; (Y.O.); (M.C.); (A.V.T.)
- Brain Cognition and Brain Disease Institute, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Li Wen
- Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK; (L.W.); (J.A.A.); (D.L.); (W.C.); (M.A.); (R.M.); (W.H.); (R.S.)
| | - Jane A. Armstrong
- Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK; (L.W.); (J.A.A.); (D.L.); (W.C.); (M.A.); (R.M.); (W.H.); (R.S.)
| | - Michael Chvanov
- Department of Molecular Physiology & Cell Signalling, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK; (Y.O.); (M.C.); (A.V.T.)
| | - Diane Latawiec
- Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK; (L.W.); (J.A.A.); (D.L.); (W.C.); (M.A.); (R.M.); (W.H.); (R.S.)
| | - Wenhao Cai
- Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK; (L.W.); (J.A.A.); (D.L.); (W.C.); (M.A.); (R.M.); (W.H.); (R.S.)
| | - Mohammad Awais
- Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK; (L.W.); (J.A.A.); (D.L.); (W.C.); (M.A.); (R.M.); (W.H.); (R.S.)
| | - Rajarshi Mukherjee
- Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK; (L.W.); (J.A.A.); (D.L.); (W.C.); (M.A.); (R.M.); (W.H.); (R.S.)
| | - Wei Huang
- Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK; (L.W.); (J.A.A.); (D.L.); (W.C.); (M.A.); (R.M.); (W.H.); (R.S.)
| | - Peter J. Gough
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA; (P.J.G.); (J.B.)
| | - John Bertin
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA; (P.J.G.); (J.B.)
| | - Alexei V. Tepikin
- Department of Molecular Physiology & Cell Signalling, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK; (Y.O.); (M.C.); (A.V.T.)
| | - Robert Sutton
- Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK; (L.W.); (J.A.A.); (D.L.); (W.C.); (M.A.); (R.M.); (W.H.); (R.S.)
| | - David N. Criddle
- Department of Molecular Physiology & Cell Signalling, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK; (Y.O.); (M.C.); (A.V.T.)
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Apoptosis: A friend or foe in mesenchymal stem cell-based immunosuppression. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021. [PMID: 34090619 DOI: 10.1016/bs.apcsb.2021.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
Mesenchymal stem cells (MSC) are adult stem cells which reside in almost all postnatal tissue where, in juxtacrine and paracrine manner, regulate phenotype and function of immune cells, maintain tissue homeostasis, attenuate on-going inflammation and promote repair and regeneration of injured tissues. Due to their capacity to suppress detrimental immune response, MSC have been considered as potentially new therapeutic agents in the treatment of autoimmune and inflammatory diseases. It was recently revealed that apoptosis may increase anti-inflammatory properties of MSC by enhancing their capacity to induce generation of immunosuppressive phenotype in macrophages and dendritic cells. Upon phagocytosis, apoptotic MSC induce generation of immunosuppressive phenotype in monocytes/macrophages and promote production of anti-inflammatory cytokines and growth factors that attenuate inflammation and facilitate repair and regeneration of injured tissues. Importantly, immunomodulation mediated by apoptotic MSC was either similar or even better than immunomodulation accomplished by viable MSC. In contrast to viable MSC, which obtain either pro- or anti-inflammatory phenotype upon engraftment in different tissue microenvironments, apoptotic MSC were not subject to changes in their immunomodulatory characteristics upon diverse stimuli, indicating their potential for clinical use. In this chapter, we summarized current knowledge about beneficial effects of apoptotic MSC in the suppression of detrimental local and systemic immune response, and we emphasized their therapeutic potential in the treatment of inflammatory diseases.
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Bellet MM, Borghi M, Pariano M, Renga G, Stincardini C, D'Onofrio F, Brancorsini S, Garaci E, Costantini C, Romani L. Thymosin alpha 1 exerts beneficial extrapulmonary effects in cystic fibrosis. Eur J Med Chem 2020; 209:112921. [PMID: 33071052 DOI: 10.1016/j.ejmech.2020.112921] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 08/12/2020] [Accepted: 10/06/2020] [Indexed: 12/12/2022]
Abstract
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding for the ion channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR). Long considered a lung disease for the devastating impact on the respiratory function, the recent diagnostic and therapeutic advances have shed the light on the extra-pulmonary manifestations of CF, including gastrointestinal, hepatobiliary and pancreatic symptoms. We have previously demonstrated that thymosin alpha1 (Tα1), a naturally occurring immunomodulatory peptide, displays multi-sided beneficial effects in CF that concur in ameliorating the lung inflammatory pathology. In the present study, by resorting to murine models of gut inflammation with clinical relevance for CF patients, we demonstrate that Tα1 can also have beneficial effects in extrapulmonary pathology. Specifically, Tα1 restored barrier integrity and immune homeostasis in the inflamed gut of CF mice as well as in mice with the metabolic syndrome, a disorder that may arise in CF patients with high caloric intake despite pancreatic sufficiency. The protective effects of Tα1 also extended to pancreas and liver, further emphasizing the beneficial effects of Tα1 in extra-pulmonary complications of CF. By performing wide-ranging multi-organ anti-inflammatory effects, Tα1 could potentially integrate current therapeutic approaches to tackle the complex symptomatology of CF disease.
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Affiliation(s)
- Marina M Bellet
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy.
| | - Monica Borghi
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy
| | - Marilena Pariano
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy
| | - Giorgia Renga
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy
| | - Claudia Stincardini
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy
| | - Fiorella D'Onofrio
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy
| | - Stefano Brancorsini
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy
| | - Enrico Garaci
- University San Raffaele and IRCCS San Raffaele, 00166, Rome, Italy
| | - Claudio Costantini
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy
| | - Luigina Romani
- Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy.
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Tryptophan Metabolism, Regulatory T Cells, and Inflammatory Bowel Disease: A Mini Review. Mediators Inflamm 2020; 2020:9706140. [PMID: 32617076 PMCID: PMC7306093 DOI: 10.1155/2020/9706140] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract resulting from the homeostasis imbalance of intestinal microenvironment, immune dysfunction, environmental and genetic factors, and so on. This disease is associated with multiple immune cells including regulatory T cells (Tregs). Tregs are a subset of T cells regulating the function of various immune cells to induce immune tolerance and maintain intestinal immune homeostasis. Tregs are correlated with the initiation and progression of IBD; therefore, strategies that affect the differentiation and function of Tregs may be promising for the prevention of IBD-associated pathology. It is worth noting that tryptophan (Trp) metabolism is effective in inducing the differentiation of Tregs through microbiota-mediated degradation and kynurenine pathway (KP), which is important for maintaining the function of Tregs. Interestingly, patients with IBD show Trp metabolism disorder in the pathological process, including changes in the concentrations of Trp and its metabolites and alteration in the activities of related catalytic enzymes. Thus, manipulation of Treg differentiation through Trp metabolism may provide a potential target for prevention of IBD. The purpose of this review is to highlight the relationship between Trp metabolism and Treg differentiation and the role of this interaction in the pathogenesis of IBD.
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Harrell CR, Jovicic N, Djonov V, Volarevic V. Therapeutic Use of Mesenchymal Stem Cell-Derived Exosomes: From Basic Science to Clinics. Pharmaceutics 2020; 12:pharmaceutics12050474. [PMID: 32456070 PMCID: PMC7313713 DOI: 10.3390/pharmaceutics12050474] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/30/2020] [Accepted: 05/11/2020] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cells (MSC) are, due to their immunosuppressive and regenerative properties, used as new therapeutic agents in cell-based therapy of inflammatory and degenerative diseases. A large number of experimental and clinical studies revealed that most of MSC-mediated beneficial effects were attributed to the effects of MSC-sourced exosomes (MSC-Exos). MSC-Exos are nano-sized extracellular vesicles that contain MSC-derived bioactive molecules (messenger RNA (mRNA), microRNAs (miRNAs)), enzymes, cytokines, chemokines, and growth factors) that modulate phenotype, function and homing of immune cells, and regulate survival and proliferation of parenchymal cells. In this review article, we emphasized current knowledge about molecular and cellular mechanisms that were responsible for MSC-Exos-based beneficial effects in experimental models and clinical trials. Additionally, we elaborated on the challenges of conventional MSC-Exos administration and proposed the use of new bioengineering and cellular modification techniques which could enhance therapeutic effects of MSC-Exos in alleviation of inflammatory and degenerative diseases.
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Affiliation(s)
- Carl Randall Harrell
- Regenerative Processing Plant, LLC, 34176 US Highway 19 N Palm Harbor, Palm Harbor, FL 34684, USA;
| | - Nemanja Jovicic
- Department of Histology and Embryology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia;
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, 2 Baltzerstrasse, 3012 Bern, Switzerland;
| | - Vladislav Volarevic
- Department for Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
- Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), Università di Catania, Via Santa Sofia 78, 95123 Catania, Italy
- Correspondence: ; Tel.: +381-34306800; Fax: +381-34306800
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Riess C, Schneider B, Kehnscherper H, Gesche J, Irmscher N, Shokraie F, Classen CF, Wirthgen E, Domanska G, Zimpfer A, Strüder D, Junghanss C, Maletzki C. Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib. Front Immunol 2020; 11:55. [PMID: 32117235 PMCID: PMC7034242 DOI: 10.3389/fimmu.2020.00055] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 01/09/2020] [Indexed: 01/08/2023] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) are the key enzymes of tryptophan (TRP) metabolism in the kynurenine pathway (KP). Both enzymes function as indicators of immunosuppression and poor survival in cancer patients. Direct or indirect targeting of either of these substances seems thus reasonable to improve therapy options for patients. In this study, glioblastoma multiforme (GBM) as well as head and neck squamous cell carcinomas (HNSCC) were examined because of their different mechanisms of spontaneous and treatment-induced immune escape. Effects on gene expression and protein levels were examined. Accompanying assessment of TRP metabolites from treated GBM cell culture supernatants was conducted. Our results show a heterogeneous and inversely correlated expression profile of TRP-metabolizing genes among GBM and HNSCC cells, with low, but inducible IDO1 expression upon IFNγ treatment. TDO2 expression was higher in GBM cells, while genes encoding kynurenine aminotransferases were mainly confined to HNSCC cells. These data indicate that the KP is active in both entities, with however different enzymes involved in TRP catabolism. Upon treatment with Temozolomide, the standard of care for GBM patients, IDO1 was upregulated. Comparable, although less pronounced effects were seen in HNSCC upon Cetuximab and conventional drugs (i.e., 5-fluorouracil, Gemcitabine). Here, IDO1 and additional genes of the KP (KYAT1, KYAT2, and KMO) were induced. Vice versa, the novel yet experimental cyclin-dependent kinase inhibitor Dinaciclib suppressed KP in both entities. Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway. These data point to limitations of conventional therapy and highlight the potential of targeted therapies to interfere with the cells' metabolism more than anticipated.
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Affiliation(s)
- Christin Riess
- University Children's Hospital, Rostock University Medical Centre, Rostock, Germany.,Institute for Medical Microbiology, Virology, and Hygiene, Rostock University Medical Centre, Rostock, Germany.,Medical Clinic III - Hematology, Oncology, Palliative Care, Department of Internal Medicine, Rostock University Medical Center, Rostock, Germany
| | - Björn Schneider
- Institute of Pathology, Rostock University Medical Center, University of Rostock, Rostock, Germany
| | - Hanna Kehnscherper
- Medical Clinic III - Hematology, Oncology, Palliative Care, Department of Internal Medicine, Rostock University Medical Center, Rostock, Germany
| | - Julia Gesche
- Medical Clinic III - Hematology, Oncology, Palliative Care, Department of Internal Medicine, Rostock University Medical Center, Rostock, Germany
| | - Nina Irmscher
- Medical Clinic III - Hematology, Oncology, Palliative Care, Department of Internal Medicine, Rostock University Medical Center, Rostock, Germany
| | - Fatemeh Shokraie
- University Children's Hospital, Rostock University Medical Centre, Rostock, Germany
| | | | - Elisa Wirthgen
- University Children's Hospital, Rostock University Medical Centre, Rostock, Germany
| | - Grazyna Domanska
- Institute of Immunology and Transfusion Medicine, University of Greifswald, Greifswald, Germany
| | - Annette Zimpfer
- Institute of Pathology, Rostock University Medical Center, University of Rostock, Rostock, Germany
| | - Daniel Strüder
- Department of Otorhinolaryngology, Head and Neck Surgery "Otto Koerner", Rostock University Medical Center, Rostock, Germany
| | - Christian Junghanss
- Medical Clinic III - Hematology, Oncology, Palliative Care, Department of Internal Medicine, Rostock University Medical Center, Rostock, Germany
| | - Claudia Maletzki
- Medical Clinic III - Hematology, Oncology, Palliative Care, Department of Internal Medicine, Rostock University Medical Center, Rostock, Germany
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Volarevic V, Markovic BS, Jankovic MG, Djokovic B, Jovicic N, Harrell CR, Fellabaum C, Djonov V, Arsenijevic N, Lukic ML. Galectin 3 protects from cisplatin-induced acute kidney injury by promoting TLR-2-dependent activation of IDO1/Kynurenine pathway in renal DCs. Theranostics 2019; 9:5976-6001. [PMID: 31534532 PMCID: PMC6735380 DOI: 10.7150/thno.33959] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 06/17/2019] [Indexed: 12/21/2022] Open
Abstract
Strategies targeting cross-talk between immunosuppressive renal dendritic cells (DCs) and T regulatory cells (Tregs) may be effective in treating cisplatin (CDDP)-induced acute kidney injury (AKI). Galectin 3 (Gal-3), expressed on renal DCs, is known as a crucial regulator of immune response in the kidneys. In this study, we investigated the role of Gal-3 for DCs-mediated expansion of Tregs in the attenuation of CDDP-induced AKI. Methods: AKI was induced in CDDP-treated wild type (WT) C57BL/6 and Gal-3 deficient (Gal-3-/-) mice. Biochemical, histological analysis, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, real-time PCR, magnetic cell sorting, flow cytometry and intracellular staining of renal-infiltrated immune cells were used to determine the differences between CDDP-treated WT and Gal-3-/- mice. Newly synthesized selective inhibitor of Gal-3 (Davanat) was used for pharmacological inhibition of Gal-3. Recombinant Gal-3 was used to demonstrate the effects of exogenously administered soluble Gal-3 on AKI progression. Pam3CSK4 was used for activation of Toll-like receptor (TLR)-2 in DCs. Cyclophosphamide or anti-CD25 antibody were used for the depletion of Tregs. 1-Methyl Tryptophan (1-MT) was used for pharmacological inhibition of Indoleamine 2,3-dioxygenase-1 (IDO1) in TLR-2-primed DCs which were afterwards used in passive transfer experiments. Results: CDDP-induced nephrotoxicity was significantly more aggravated in Gal-3-/- mice. Significantly reduced number of immunosuppressive TLR-2 and IDO1-expressing renal DCs, lower serum levels of KYN, decreased presence of IL-10-producing Tregs and significantly higher number of inflammatory IFN-γ and IL-17-producing neutrophils, Th1 and Th17 cells were observed in the CDDP-injured kidneys of Gal-3-/- mice. Pharmacological inhibitor of Gal-3 aggravated CDDP-induced AKI in WT animals while recombinant Gal-3 attenuated renal injury and inflammation in CDDP-treated Gal-3-/- mice. CDDP-induced apoptosis, driven by Bax and caspase-3, was aggravated in Gal-3-/- animals and in WT mice that received Gal-3 inhibitor (CDDP+Davanat-treated mice). Recombinant Gal-3 managed to completely attenuate CDDP-induced apoptosis in CDDP-injured kidneys of Gal-3-/- mice. Genetic deletion as well as pharmacological inhibition of Gal-3 in renal DCs remarkably reduced TLR-2-dependent activation of IDO1/KYN pathway in these cells diminishing their capacity to prevent transdifferentiation of Tregs in inflammatory Th1 and Th17 cells. Additionally, Tregs generated by Gal-3 deficient DCs were not able to suppress production of IFN-γ and IL-17 in activated neutrophils. TLR-2-primed DCs significantly enhanced capacity of Tregs for attenuation of CDDP-induced AKI and inflammation and expression of Gal-3 on TLR-2-primed DCs was crucially important for their capacity to enhance nephroprotective and immunosuppressive properties of Tregs. Adoptive transfer of TLR-2-primed WTDCs significantly expanded Tregs in the kidneys of CDDP-treated WT and Gal-3-/- recipients resulting in the suppression of IFN-γ and IL-17-driven inflammation and alleviation of AKI. Importantly, this phenomenon was not observed in CDDP-treated WT and Gal-3-/- recipients of TLR-2-primed Gal-3-/-DCs. Gal-3-dependent nephroprotective and immunosuppressive effects of renal DCs was due to the IDO1-induced expansion of renal Tregs since either inhibition of IDO1 activity in TLR-2-primed DCs or depletion of Tregs completely diminished DCs-mediated attenuation of CDDP-induced AKI. Conclusions: Gal-3 protects from CDDP-induced AKI by promoting TLR-2-dependent activation of IDO1/KYN pathway in renal DCs resulting in increased expansion of immunosuppressive Tregs in injured kidneys. Activation of Gal-3:TLR-2:IDO1 pathway in renal DCs should be further explored as new therapeutic approach for DC-based immunosuppression of inflammatory renal diseases.
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Galectin-3 Regulates Indoleamine-2,3-dioxygenase-Dependent Cross-Talk between Colon-Infiltrating Dendritic Cells and T Regulatory Cells and May Represent a Valuable Biomarker for Monitoring the Progression of Ulcerative Colitis. Cells 2019; 8:cells8070709. [PMID: 31336879 PMCID: PMC6678202 DOI: 10.3390/cells8070709] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/30/2019] [Accepted: 07/03/2019] [Indexed: 12/16/2022] Open
Abstract
Galectin-3 regulates numerous biological processes in the gut. We investigated molecular mechanisms responsible for the Galectin-3-dependent regulation of colon inflammation and evaluated whether Galectin-3 may be used as biomarker for monitoring the progression of ulcerative colitis (UC). The differences in disease progression between dextran sodium sulphate-treated wild type and Galectin-3-deficient mice were investigated and confirmed in clinical settings, in 65 patients suffering from mild, moderate, and severe colitis. During the induction phase of colitis, Galectin-3 promoted interleukin-1β-induced polarization of colonic macrophages towards inflammatory phenotype. In the recovery phase of colitis, Galectin-3 was required for the immunosuppressive function of regulatory dendritic cells (DCs). Regulatory DCs in Galectin-3:Toll-like receptor-4:Kynurenine-dependent manner promoted the expansion of colon-infiltrated T regulatory cells (Tregs) and suppressed Th1 and Th17 cell-driven colon inflammation. Concentration of Galectin-3 in serum and stool samples of UC patients negatively correlated with clinical, endoscopic, and histological parameters of colitis. The cutoff serum values of Galectin-3 that allowed the discrimination of mild from moderate and moderate from severe colitis were 954 pg/mL and 580 pg/mL, respectively. Fecal levels of Galectin-3 higher than 553.44 pg/mL indicated attenuation of UC. In summing up, Galectin-3 regulates the cross-talk between colon-infiltrating DCs and Tregs and represents a new biomarker for monitoring the progression of UC.
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Harrell CR, Fellabaum C, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. Molecular Mechanisms Responsible for Therapeutic Potential of Mesenchymal Stem Cell-Derived Secretome. Cells 2019; 8:cells8050467. [PMID: 31100966 PMCID: PMC6562906 DOI: 10.3390/cells8050467] [Citation(s) in RCA: 304] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 04/28/2019] [Accepted: 04/30/2019] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cell (MSC)-sourced secretome, defined as the set of MSC-derived bioactive factors (soluble proteins, nucleic acids, lipids and extracellular vesicles), showed therapeutic effects similar to those observed after transplantation of MSCs. MSC-derived secretome may bypass many side effects of MSC-based therapy, including unwanted differentiation of engrafted MSCs. In contrast to MSCs which had to be expanded in culture to reach optimal cell number for transplantation, MSC-sourced secretome is immediately available for treatment of acute conditions, including fulminant hepatitis, cerebral ischemia and myocardial infarction. Additionally, MSC-derived secretome could be massively produced from commercially available cell lines avoiding invasive cell collection procedure. In this review article we emphasized molecular and cellular mechanisms that were responsible for beneficial effects of MSC-derived secretomes in the treatment of degenerative and inflammatory diseases of hepatobiliary, respiratory, musculoskeletal, gastrointestinal, cardiovascular and nervous system. Results obtained in a large number of studies suggested that administration of MSC-derived secretomes represents a new, cell-free therapeutic approach for attenuation of inflammatory and degenerative diseases. Therapeutic effects of MSC-sourced secretomes relied on their capacity to deliver genetic material, growth and immunomodulatory factors to the target cells enabling activation of anti-apoptotic and pro-survival pathways that resulted in tissue repair and regeneration.
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Affiliation(s)
| | | | - Nemanja Jovicic
- Department for Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000 Kragujevac, Serbia.
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012 Bern, Switzerland.
| | - Nebojsa Arsenijevic
- Department for Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000 Kragujevac, Serbia.
| | - Vladislav Volarevic
- Department for Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000 Kragujevac, Serbia.
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