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Fischer B, Kolb A, Focaccia E, Kübelbeck T, Klein M, Löck D, Bork F, Engelmann F, Casari M, Mazza E, Deppermann C, Weber ANR, Wittmann M, Schittek B, Schulze-Osthoff K, Kramer D. NOD2-induced IκBζ mediates a protective host response against epicutaneous Staphylococcus aureus infection. J Invest Dermatol 2025:S0022-202X(25)00494-4. [PMID: 40412468 DOI: 10.1016/j.jid.2025.04.036] [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: 12/06/2024] [Revised: 04/06/2025] [Accepted: 04/09/2025] [Indexed: 05/27/2025]
Abstract
IκBζ, an atypical and largely unknown member of the IκB family, is a transcriptional coactivator of selective immune functions. Here, we investigated the role of keratinocyte-derived IκBζ upon infection with a multidrug-resistant S. aureus strain. Infection of keratinocytes rapidly induced IκBζ expression, leading to an elevated expression of antimicrobial peptides, IL-17/IL-36-responsive genes, and proteins involved in skin barrier function. Conversely, loss of IκBζ resulted in increased S. aureus internalization, epidermal tissue damage, and severe skin infections in vivo. This impaired host defense upon IκBζ depletion was characterized by reduced antimicrobial peptide expression, and diminished recruitment of neutrophils and CD4+ T-cells. Importantly, S. aureus-induced IκBζ expression required the internalization of the bacteria and its sensing by the intracellular receptor NOD2, which triggered IκBζ and its target gene expression. Thus, we identified NOD2-IκBζ signaling as a novel pathway acting as a key mediator for a protective host defense against pathogenic S. aureus infections in the skin.
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Affiliation(s)
- Berenice Fischer
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany
| | - Antonia Kolb
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany
| | - Enrico Focaccia
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany
| | - Tanja Kübelbeck
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany
| | - Matthias Klein
- Institute of Immunology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany; Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany
| | - Dagmar Löck
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany
| | - Francesca Bork
- Institute of Immunology, Department of Innate Immunity, Eberhard Karls-University, Tübingen, Germany
| | - Franziska Engelmann
- Interfaculty Institute for Biochemistry, Eberhard Karls-University Tübingen, Germany
| | - Martina Casari
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Elisa Mazza
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany
| | - Carsten Deppermann
- Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Alexander N R Weber
- Institute of Immunology, Department of Innate Immunity, Eberhard Karls-University, Tübingen, Germany; iFIT - Cluster of Excellence (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Germany; CMFI - Cluster of Excellence (EXC 2124) "Controlling Microbes to Fight Infection", University of Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, 72076 Tübingen, Germany
| | - Miriam Wittmann
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany; Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany
| | - Birgit Schittek
- Department of Dermatology, Eberhard Karls-University, Tübingen, Germany
| | - Klaus Schulze-Osthoff
- Interfaculty Institute for Biochemistry, Eberhard Karls-University Tübingen, Germany; iFIT - Cluster of Excellence (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, 72076 Tübingen, Germany
| | - Daniela Kramer
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany; Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
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2
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Cai X. NOD2-NLRP3 Axis and Asthma. J Asthma Allergy 2025; 18:769-777. [PMID: 40433101 PMCID: PMC12106908 DOI: 10.2147/jaa.s526788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Patients with asthma frequently experience recurrent symptoms including coughing, wheezing, shortness of breath, and chest tightness. Asthma is a common public health concern. It is characterized by chronic airway inflammation. However, The pathogenesis of asthma is complex. Inflammasomes are signaling platforms that regulate the inflammatory response. There is a correlation between inflammasomes and asthma. Pattern recognition receptors recognize danger signals and participate in inflammasome activation. Nucleotide-binding and oligomerization domain-containing 2 (NOD2), a pattern recognition receptor, senses microbial components and triggers immune responses. There have been studies showing a correlation between NOD2 and asthma. The nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) participates in the formation of inflammasomes. NLRP3 are involved in asthma pathogenesis. In this review, we discuss the roles of NOD2 and NLRP3 in the pathogenesis of asthma.
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Affiliation(s)
- Xulong Cai
- Department of Pediatrics, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, 224000, People’s Republic of China
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Kastner L, Kandalaft W, Mahant Mahant A, Crimella J, Hakim S, Peng X, Isakoff MS, Hayashi M, Loeb DM. Cytokine Profiling of Children, Adolescents, and Young Adults Newly Diagnosed with Sarcomas Demonstrates a Role for IL-1β in Osteosarcoma Metastasis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.04.05.25325205. [PMID: 40297413 PMCID: PMC12036375 DOI: 10.1101/2025.04.05.25325205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Background Sarcomas are a heterogeneous group of mesenchymal tumors frequently diagnosed in pediatric and young adult patients. These tumors respond poorly to conventional immunotherapy, though the precise reason for this is not known. We sought to characterize the systemic immune response to sarcomas by measuring the levels of circulating cytokines in the plasma of sarcoma patients, testing the hypothesis that the natures of a patient's immune response to their tumor directly affects outcome. Methods Plasma was collected from newly diagnosed, treatment-naive pediatric sarcoma patients participating in an ongoing clinical trial, MCC20320. A panel of 18 cytokines was selected and cytokine levels were measured using the Luminex platform. Cytokine levels were analyzed based on clinicopathological parameters such as gender, age, stage, and survival. Results We found that the cytokine profile in patients newly diagnosed with sarcoma is distinct from healthy controls, but different sarcomas were not distinguishable. Patients with osteosarcoma who had elevated levels of multiple cytokines had inferior overall survival compared to those with fewer or no elevated levels. Similarly, elevated levels of individual cytokines and chemokines, including IL-24, CXCL5, and CXCL10, were associated with inferior event-free or overall survival in patients with osteosarcoma. Perhaps most significantly, elevated IL-1β at diagnosis was associated with metastatic presentation and inferior event-free survival in patients with osteosarcoma. Conclusion These findings suggest that pediatric sarcoma patients mount a systemic immune response that may affect event-free or overall survival. IL-1β in particular may be a valuable target for immunotherapy for osteosarcoma patients.
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Affiliation(s)
- Laurel Kastner
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461
| | - William Kandalaft
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461
| | | | | | - Sydney Hakim
- Department of Pediatrics-Hematology/Oncology and Bone Marrow Transplantation, University of Colorado, Aurora, Colorado 80045
| | - Xiao Peng
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461
| | | | - Masanori Hayashi
- Department of Pediatrics-Hematology/Oncology and Bone Marrow Transplantation, University of Colorado, Aurora, Colorado 80045
| | - David M Loeb
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461
- Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461
- Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, NY 10461
- Marilyn and Stanley M. Katz Institute for Immunotherapy for Cancer and Inflammatory Disorders, Albert Einstein College of Medicine, Bronx, NY 10461
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Schafer RM, Giancotti LA, Chrivia JC, Li Y, Mufti F, Kufer TA, Zhang J, Doyle TM, Salvemini D. CARTp/GPR160 mediates behavioral hypersensitivities in mice through NOD2. Pain 2025; 166:902-915. [PMID: 39356206 DOI: 10.1097/j.pain.0000000000003418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 08/27/2024] [Indexed: 10/03/2024]
Abstract
ABSTRACT Neuropathic pain is a debilitating chronic condition that remains difficult to treat. More efficacious and safer therapeutics are needed. A potential target for therapeutic intervention recently identified by our group is the G-protein coupled receptor 160 (GPR160) and the cocaine- and amphetamine-regulated transcript peptide (CARTp) as a ligand for GPR160. Intrathecal administration of CARTp in rodents causes GPR160-dependent behavioral hypersensitivities. However, the molecular and biochemical mechanisms underpinning GPR160/CARTp-induced behavioral hypersensitivities in the spinal cord remain poorly understood. Therefore, we performed an unbiased RNA transcriptomics screen of dorsal horn spinal cord (DH-SC) tissues harvested at the time of peak CARTp-induced hypersensitivities and identified nucleotide-binding oligomerization domain-containing protein 2 ( Nod2 ) as a gene that is significantly upregulated. Nucleotide-binding oligomerization domain-containing protein 2 is a cytosolic pattern-recognition receptor involved in activating the immune system in response to bacterial pathogens. While NOD2 is well studied under pathogenic conditions, the role of NOD2-mediated responses in nonpathogenic settings is still not well characterized. Genetic and pharmacological approaches reveal that CARTp-induced behavioral hypersensitivities are driven by NOD2, with co-immunoprecipitation studies indicating an interaction between GPR160 and NOD2. Cocaine- and amphetamine-regulated transcript peptide-induced behavioral hypersensitivities are independent of receptor-interacting protein kinase 2 (RIPK2), a common adaptor protein to NOD2. Immunofluorescence studies found NOD2 co-expressed with endothelial cells rather than glial cells, implicating potential roles for CARTp/NOD2 signaling in these cells. While these findings are based only on studies with male mice, our results identify a novel pathway by which CARTp causes behavioral hypersensitivities in the DH-SC through NOD2 and highlights the importance of NOD2-mediated responses in nonpathogenic settings.
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Affiliation(s)
- Rachel M Schafer
- Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, St. Louis, MO, United States
- Institute for Translational Neuroscience, Saint Louis University, St. Louis, MO, United States
| | - Luigino A Giancotti
- Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, St. Louis, MO, United States
- Institute for Translational Neuroscience, Saint Louis University, St. Louis, MO, United States
| | - John C Chrivia
- Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, St. Louis, MO, United States
- Institute for Translational Neuroscience, Saint Louis University, St. Louis, MO, United States
| | - Ying Li
- Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, St. Louis, MO, United States
- Institute for Translational Neuroscience, Saint Louis University, St. Louis, MO, United States
| | - Fatma Mufti
- Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, St. Louis, MO, United States
- Institute for Translational Neuroscience, Saint Louis University, St. Louis, MO, United States
| | - Thomas A Kufer
- Department of Immunology, Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - Jinsong Zhang
- Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, St. Louis, MO, United States
| | - Timothy M Doyle
- Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, St. Louis, MO, United States
- Institute for Translational Neuroscience, Saint Louis University, St. Louis, MO, United States
| | - Daniela Salvemini
- Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, St. Louis, MO, United States
- Institute for Translational Neuroscience, Saint Louis University, St. Louis, MO, United States
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5
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Sugimoto W, Inoue H, Sougawa N, Goda S, Nishiura A. MDP/NOD2 enhances RANKL-induced osteoclast differentiation of RAW264.7 cells. J Oral Biosci 2025; 67:100630. [PMID: 39956215 DOI: 10.1016/j.job.2025.100630] [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: 10/03/2024] [Revised: 02/10/2025] [Accepted: 02/10/2025] [Indexed: 02/18/2025]
Abstract
OBJECTIVE Receptor activator of nuclear factor-κB ligand (RANKL) is intimately involved in regulating bone remodeling during osteoclast differentiation and promotion of osteoclast function. Upon binding to its receptor, RANK, RANKL activates various signaling cascades that induce osteoclast differentiation of osteoclast precursor cells into osteoclasts. In the innate immune system, host pattern recognition receptors, such as Toll-like receptors and nucleotide-binding oligomerization domain-like receptors (NLRs), detect pathogen-associated molecular patterns and elicit an immune response. The NLR, nucleotide-binding oligomerization domain 2 (NOD2), is known to bind muramyl dipeptide (MDP) and regulate inflammatory responses via nuclear factor-κB (NF-κB). The objective of this study was to investigate the effect of MDP on RANKL stimulation of osteoclast differentiation to elucidate the mechanism of bone resorption in a bacterial infection-induced inflammation model. METHODS The extent of osteoclast formation in MDP-stimulated RAW 264.7 cells was assessed using a tartrate-resistant acid phosphatase activity assay. The protein levels of intracellular signaling molecules were assessed by western blotting. RESULTS In RAW 264.7 cells, MDP stimulation did not affect the expression of RANK. MDP enhanced the expression of osteoclast-specific proteins, such as nuclear factor of activated T cells 1 (NFATc1) and cathepsin K, which are osteoclast differentiation markers, in RANKL-stimulated RAW 267.4 cells. Furthermore, JSH23, an NF-κB inhibitor, suppressed the expression of NFATc1 after co-stimulation with MDP and RANKL. CONCLUSION MDP promoted osteoclast differentiation in RAW 267.4 cells by upregulating the activators, NF-κB and NFATc1, which are important for osteoclast differentiation, through enhancement of the RANKL signaling pathway.
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Affiliation(s)
- Wakana Sugimoto
- Graduate School of Dentistry, Department of Orthodontics, Osaka Dental University, Osaka, Japan
| | - Hiroshi Inoue
- Department of Physiology, Osaka Dental University, Osaka, Japan.
| | - Nagako Sougawa
- Department of Physiology, Osaka Dental University, Osaka, Japan
| | - Seiji Goda
- Department of Physiology, Osaka Dental University, Osaka, Japan.
| | - Aki Nishiura
- Department of Orthodontics, Osaka Dental University, Osaka, Japan
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6
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Hu M, Xu Y, Wang Y, Huang Z, Wang L, Zeng F, Qiu B, Liu Z, Yuan P, Wan Y, Ge S, Zhong D, Xiao S, Luo R, He J, Sun M, Zhuang X, Guo N, Cui C, Gao J, Zhou H, He X. Gut microbial-derived N-acetylmuramic acid alleviates colorectal cancer via the AKT1 pathway. Gut 2025:gutjnl-2024-332891. [PMID: 40015949 DOI: 10.1136/gutjnl-2024-332891] [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: 05/17/2024] [Accepted: 02/15/2025] [Indexed: 03/01/2025]
Abstract
BACKGROUND Gut microbial metabolites are recognised as critical effector molecules that influence the development of colorectal cancer (CRC). Peptidoglycan fragments (PGFs) produced by microbiota play a crucial role in maintaining intestinal homeostasis, but their role in CRC remains unclear. OBJECTIVE Here, we aimed to explore the potential contribution of PGFs in intestinal tumourigenesis. DESIGN The relative abundance of peptidoglycan synthase and hydrolase genes was assessed by metagenomic analysis. Specific PGFs in the faeces and serum of CRC patients were quantified using targeted mass spectrometry. The effects of PGF on intestinal tumourigenesis were systematically evaluated using various murine models of CRC and organoids derived from CRC patients. Downstream molecular targets were screened and evaluated using proteome microarray, transcriptome sequencing and rescue assays. RESULTS Metagenomic analysis across seven independent cohorts (n=1121) revealed a comprehensive reduction in peptidoglycan synthase gene relative abundance in CRC patients. Targeted mass spectrometry identified significant depletion of a specific PGF, N-acetylmuramic acid (NAM) in CRC patients, which decreased as tumours progressed (p<0.001). NAM significantly inhibits intestinal tumourigenesis in various models, including Apc Min/+, AOM/DSS-treated and MC38 tumour-bearing mice. Additionally, NAM inhibits the growth of patient-derived CRC organoids in a concentration-dependent manner. Mechanistically, NAM inhibits the activation of AKT1 by directly binding to it and blocking its phosphorylation, which is a partial mediator of NAM's anticancer effects. CONCLUSION The PGF NAM protects against intestinal tumourigenesis by targeting the AKT1 signalling pathway. NAM may serve as a novel potential preventive and therapeutic biomarker against CRC.
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Affiliation(s)
- Mengyao Hu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yi Xu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuqing Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhenhe Huang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lei Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Fanan Zeng
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Bowen Qiu
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zefeng Liu
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Peibo Yuan
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yu Wan
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Shuang Ge
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Dian Zhong
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Siyu Xiao
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Rongrong Luo
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jiaqi He
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Meiling Sun
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoduan Zhuang
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Nannan Guo
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chunhui Cui
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jie Gao
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
- The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Hongwei Zhou
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaolong He
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Southern Medical University, Guangzhou, Guangdong, China
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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7
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Bharadwaj R, Jaiswal S, Silverman N. Cytosolic delivery of innate immune agonists. Trends Immunol 2024; 45:1001-1014. [PMID: 39567309 PMCID: PMC11624987 DOI: 10.1016/j.it.2024.10.007] [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: 09/12/2024] [Revised: 10/19/2024] [Accepted: 10/21/2024] [Indexed: 11/22/2024]
Abstract
Solute carrier proteins (SLCs) are pivotal for maintaining cellular homeostasis by transporting small molecules across cellular membranes. Recent discoveries have uncovered their involvement in modulating innate immunity, particularly within the cytosol. We review emerging evidence that links SLC transporters to cytosolic innate immune recognition and highlight their role in regulating inflammation. We explore how SLC transporters influence the activation of endosomal Toll-like receptors, cytosolic NODs, and STING sensors. Understanding the contribution of SLCs to innate immune recognition provides insight into their fundamental biological functions and opens new avenues to develop possible therapeutic interventions for autoimmune and inflammatory diseases. This review aims to discuss current knowledge and identify key gaps in this rapidly evolving field.
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Affiliation(s)
- Ravi Bharadwaj
- Division of Infectious Diseases and Immunology, Program in Innate Immunity, Department of Medicine, UMass Chan Medical School, Worcester, MA 01605, USA
| | - Swati Jaiswal
- Division of Infectious Diseases and Immunology, Program in Innate Immunity, Department of Medicine, UMass Chan Medical School, Worcester, MA 01605, USA
| | - Neal Silverman
- Division of Infectious Diseases and Immunology, Program in Innate Immunity, Department of Medicine, UMass Chan Medical School, Worcester, MA 01605, USA.
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8
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Liu X, Ren Z, Tan C, Núñez-Santana FL, Kelly ME, Yan Y, Sun H, Abdala-Valencia H, Yang W, Wu Q, Toyoda T, Milisav M, Casalino-Matsuda SM, Lecuona E, Cerier EJ, Heung LJ, Abazeed ME, Perlman H, Gao R, Chandel NS, Budinger GS, Bharat A. Inducible CCR2+ nonclassical monocytes mediate the regression of cancer metastasis. J Clin Invest 2024; 134:e179527. [PMID: 39545417 PMCID: PMC11563681 DOI: 10.1172/jci179527] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 09/26/2024] [Indexed: 11/17/2024] Open
Abstract
A major limitation of immunotherapy is the development of resistance resulting from cancer-mediated inhibition of host lymphocytes. Cancer cells release CCL2 to recruit classical monocytes expressing its receptor CCR2 for the promotion of metastasis and resistance to immunosurveillance. In the circulation, some CCR2-expressing classical monocytes lose CCR2 and differentiate into intravascular nonclassical monocytes that have anticancer properties but are unable to access extravascular tumor sites. We found that in mice and humans, an ontogenetically distinct subset of naturally underrepresented CCR2-expressing nonclassical monocytes was expanded during inflammatory states such as organ transplant and COVID-19 infection. These cells could be induced during health by treatment of classical monocytes with small-molecule activators of NOD2. The presence of CCR2 enabled these inducible nonclassical monocytes to infiltrate both intra- and extravascular metastatic sites of melanoma, lung, breast, and colon cancer in murine models, and they reversed the increased susceptibility of Nod2-/- mutant mice to cancer metastasis. Within the tumor colonies, CCR2+ nonclassical monocytes secreted CCL6 to recruit NK cells that mediated tumor regression, independent of T and B lymphocytes. Hence, pharmacological induction of CCR2+ nonclassical monocytes might be useful for immunotherapy-resistant cancers.
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Affiliation(s)
- Xianpeng Liu
- Division of Thoracic Surgery/Canning Thoracic Institute, Feinberg School of Medicine, Northwestern University/Northwestern Medicine, Chicago, Illinois, USA
| | | | - Can Tan
- Division of Cardiology, Department of Medicine, and
| | - Félix L. Núñez-Santana
- Division of Thoracic Surgery/Canning Thoracic Institute, Feinberg School of Medicine, Northwestern University/Northwestern Medicine, Chicago, Illinois, USA
| | - Megan E. Kelly
- Division of Thoracic Surgery/Canning Thoracic Institute, Feinberg School of Medicine, Northwestern University/Northwestern Medicine, Chicago, Illinois, USA
| | - Yuanqing Yan
- Division of Thoracic Surgery/Canning Thoracic Institute, Feinberg School of Medicine, Northwestern University/Northwestern Medicine, Chicago, Illinois, USA
| | - Haiying Sun
- Division of Thoracic Surgery/Canning Thoracic Institute, Feinberg School of Medicine, Northwestern University/Northwestern Medicine, Chicago, Illinois, USA
| | - Hiam Abdala-Valencia
- Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Wenbin Yang
- Division of Thoracic Surgery/Canning Thoracic Institute, Feinberg School of Medicine, Northwestern University/Northwestern Medicine, Chicago, Illinois, USA
| | - Qiang Wu
- Division of Thoracic Surgery/Canning Thoracic Institute, Feinberg School of Medicine, Northwestern University/Northwestern Medicine, Chicago, Illinois, USA
| | - Takahide Toyoda
- Division of Thoracic Surgery/Canning Thoracic Institute, Feinberg School of Medicine, Northwestern University/Northwestern Medicine, Chicago, Illinois, USA
| | - Marija Milisav
- Division of Thoracic Surgery/Canning Thoracic Institute, Feinberg School of Medicine, Northwestern University/Northwestern Medicine, Chicago, Illinois, USA
| | - S. Marina Casalino-Matsuda
- Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Emilia Lecuona
- Division of Thoracic Surgery/Canning Thoracic Institute, Feinberg School of Medicine, Northwestern University/Northwestern Medicine, Chicago, Illinois, USA
| | - Emily Jeong Cerier
- Division of Thoracic Surgery/Canning Thoracic Institute, Feinberg School of Medicine, Northwestern University/Northwestern Medicine, Chicago, Illinois, USA
| | - Lena J. Heung
- Division of Infectious Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | | | | | - Ruli Gao
- Department of Biochemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Navdeep S. Chandel
- Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - G.R. Scott Budinger
- Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Ankit Bharat
- Division of Thoracic Surgery/Canning Thoracic Institute, Feinberg School of Medicine, Northwestern University/Northwestern Medicine, Chicago, Illinois, USA
- Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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9
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Tezcan G, Yakar N, Hasturk H, Van Dyke TE, Kantarci A. Resolution of chronic inflammation and cancer. Periodontol 2000 2024; 96:229-249. [PMID: 39177291 DOI: 10.1111/prd.12603] [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: 06/13/2024] [Revised: 07/26/2024] [Accepted: 08/09/2024] [Indexed: 08/24/2024]
Abstract
Chronic inflammation poses challenges to effective cancer treatment. Although anti-inflammatory therapies have shown short-term benefits, their long-term implications may be unfavorable because they fail to initiate the necessary inflammatory responses. Recent research underscores the promise of specialized pro-resolving mediators, which play a role in modulating the cancer microenvironment by promoting the resolution of initiated inflammatory processes and restoring tissue hemostasis. This review addresses current insights into how inflammation contributes to cancer pathogenesis and explores recent strategies to resolve inflammation associated with cancer.
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Affiliation(s)
- Gulcin Tezcan
- ADA Forsyth Institute, Cambridge, Massachusetts, USA
- Department of Fundamental Sciences, Faculty of Dentistry, Bursa Uludag University, Bursa, Turkey
| | - Nil Yakar
- ADA Forsyth Institute, Cambridge, Massachusetts, USA
| | - Hatice Hasturk
- ADA Forsyth Institute, Cambridge, Massachusetts, USA
- Department of Oral Microbiology and Infection, Harvard School of Dental Medicine, Boston, Massachusetts, USA
| | - Thomas E Van Dyke
- ADA Forsyth Institute, Cambridge, Massachusetts, USA
- Department of Oral Microbiology and Infection, Harvard School of Dental Medicine, Boston, Massachusetts, USA
| | - Alpdogan Kantarci
- ADA Forsyth Institute, Cambridge, Massachusetts, USA
- Department of Oral Microbiology and Infection, Harvard School of Dental Medicine, Boston, Massachusetts, USA
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10
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Delyea CJ, Forster MD, Luo S, Dubrule BE, Julien O, Bhavsar AP. The Salmonella Effector SspH2 Facilitates Spatially Selective Ubiquitination of NOD1 to Enhance Inflammatory Signaling. Biochemistry 2024; 63:2266-2279. [PMID: 39189508 PMCID: PMC11412229 DOI: 10.1021/acs.biochem.4c00380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 08/28/2024]
Abstract
As part of its pathogenesis, Salmonella enterica serovar Typhimurium delivers effector proteins into host cells. One effector is SspH2, a member of the so-called novel E3 ubiquitin ligase family, that interacts with and enhances, NOD1 pro-inflammatory signaling, though the underlying mechanisms are unclear. Here, we report that SspH2 interacts with multiple members of the NLRC family to enhance pro-inflammatory signaling by targeted ubiquitination. We show that SspH2 modulates host innate immunity by interacting with both NOD1 and NOD2 in mammalian epithelial cell culture via the NF-κB pathway. Moreover, purified SspH2 and NOD1 directly interact, where NOD1 potentiates SspH2 E3 ubiquitin ligase activity. Mass spectrometry and mutational analyses identified four key lysine residues in NOD1 that are required for its enhanced activation by SspH2, but not its basal activity. These critical lysine residues are positioned in the same region of NOD1 and define a surface on the receptor that appears to be targeted by SspH2. Overall, this work provides evidence for post-translational modification of NOD1 by ubiquitin and uncovers a unique mechanism of spatially selective ubiquitination to enhance the activation of an archetypal NLR.
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Affiliation(s)
- Cole J. Delyea
- Department
of Medical Microbiology and Immunology, Faculty of Medicine &
Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | - Malcolm D. Forster
- Department
of Medical Microbiology and Immunology, Faculty of Medicine &
Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | - Shu Luo
- Department
of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - Bradley E. Dubrule
- Department
of Medical Microbiology and Immunology, Faculty of Medicine &
Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | - Olivier Julien
- Department
of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - Amit P. Bhavsar
- Department
of Medical Microbiology and Immunology, Faculty of Medicine &
Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
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11
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Xu Y, Lin F, Liao G, Sun J, Chen W, Zhang L. Ripks and Neuroinflammation. Mol Neurobiol 2024; 61:6771-6787. [PMID: 38349514 DOI: 10.1007/s12035-024-03981-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 01/20/2024] [Indexed: 08/22/2024]
Abstract
Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation. Activation of RIPK1 promotes neuroinflammation. RIPK1 and RIPK3 are responsible for the control of cell death, including apoptosis, necrosis, and inflammation. RIPK1 and RIPK3 regulate inflammatory responses through the release of damage in necroptosis. RIPK1 and RIPK3 regulate inflammatory responses by releasing damage-associated molecular patterns (DAMPs) during necrosis. In addition, activated RIPK1 nuclear translocation and its interaction with the BAF complex leads to upregulation of chromatin modification and inflammatory gene expression, thereby triggering inflammation. Although RIPK2 is not directly involved in regulating cell death, it is considered an essential target for treating neurological inflammation. When the peptidoglycan receptor detects peptidoglycan IE-DAP or MDP in bacteria, it prompts NOD1 and NOD2 to recruit RIPK2 and activate the XIAP E3 ligase. This leads to the K63 ubiquitination of RIPK2. This is followed by LUBAC-mediated linear ubiquitination, which activates NF-KB and MAPK pathways to produce cytokines and chemokines. In conclusion, there are seven known members of the RIPK family, but RIPK4, RIPK5, RIPK6, and RIPK7 have not been linked to neuroinflammation. This article seeks to explore the potential of RIPK1, RIPK2, and RIPK3 kinases as therapeutic interventions for neuroinflammation, which is associated with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ischemic stroke, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI).
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Affiliation(s)
- Yue Xu
- Department of Cerebrovascular Disease, Sun Yat-Sen University, The Fifth Affiliated Hospital, Zhuhai, 519000, Guangdong, People's Republic of China
| | - Feng Lin
- Department of Cerebrovascular Disease, Sun Yat-Sen University, The Fifth Affiliated Hospital, Zhuhai, 519000, Guangdong, People's Republic of China
| | - Guolei Liao
- Department of Cerebrovascular Disease, Sun Yat-Sen University, The Fifth Affiliated Hospital, Zhuhai, 519000, Guangdong, People's Republic of China
| | - Jiaxing Sun
- Department of Cerebrovascular Disease, Sun Yat-Sen University, The Fifth Affiliated Hospital, Zhuhai, 519000, Guangdong, People's Republic of China
| | - Wenli Chen
- Department of Pharmacy, Sun Yat-Sen University, The Fifth Affiliated Hospital, Zhuhai, 519000, Guangdong, People's Republic of China.
| | - Lei Zhang
- Department of Cerebrovascular Disease, Sun Yat-Sen University, The Fifth Affiliated Hospital, Zhuhai, 519000, Guangdong, People's Republic of China.
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12
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Putnik R, Zhou J, Irnov I, Garner E, Liu M, Bersch KL, Jacobs-Wagner C, Grimes CL. Synthesis of a Borrelia burgdorferi-Derived Muropeptide Standard Fragment Library. Molecules 2024; 29:3297. [PMID: 39064876 PMCID: PMC11279244 DOI: 10.3390/molecules29143297] [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: 05/29/2024] [Revised: 07/01/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
The interplay between the human innate immune system and bacterial cell wall components is pivotal in understanding diseases such as Crohn's disease and Lyme arthritis. Lyme disease, caused by Borrelia burgdorferi, is the most prevalent tick-borne illness in the United States, with a substantial number of cases reported annually. While antibiotic treatments are generally effective, approximately 10% of Lyme disease cases develop persistent arthritis, suggesting a dysregulated host immune response. We have previously identified a link between the immunogenic B. burgdorferi peptidoglycan (PG) and Lyme arthritis and showed that this pathogen sheds significant amounts of PG fragments during growth. Here, we synthesize these PG fragments, including ornithine-containing monosaccharides and disaccharides, to mimic the unique composition of Borrelia cell walls, using reproducible and rigorous synthetic methods. This synthetic approach allows for the modular preparation of PG derivatives, providing a diverse library of well-defined fragments. These fragments will serve as valuable tools for investigating the role of PG-mediated innate immune response in Lyme disease and aid in the development of improved diagnostic methods and treatment strategies.
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Affiliation(s)
- Rachel Putnik
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
| | - Junhui Zhou
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
| | - Irnov Irnov
- Department of Biology, Stanford University, Stanford, CA 94305, USA
| | - Elise Garner
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
| | - Min Liu
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
| | - Klare L. Bersch
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
| | - Christine Jacobs-Wagner
- Department of Biology, Stanford University, Stanford, CA 94305, USA
- Sarafan Chemistry, Engineering, and Medicine for Human Health Institute, Stanford University, Stanford, CA 94305, USA
- Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA 94305, USA
- Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA
| | - Catherine Leimkuhler Grimes
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
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13
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Celik A, Beyer I, Fiedler D. An Uncommon Phosphorylation Mode Regulates the Activity and Protein Interactions of N-Acetylglucosamine Kinase. J Am Chem Soc 2024; 146:14807-14815. [PMID: 38733353 PMCID: PMC11140747 DOI: 10.1021/jacs.4c03069] [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: 03/01/2024] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024]
Abstract
While the function of protein phosphorylation in eukaryotic cell signaling is well established, the role of a closely related modification, protein pyrophosphorylation, is just starting to surface. A recent study has identified several targets of endogenous protein pyrophosphorylation in mammalian cell lines, including N-acetylglucosamine kinase (NAGK). Here, a detailed functional analysis of NAGK phosphorylation and pyrophosphorylation on serine 76 (S76) has been conducted. This analysis was enabled by using amber codon suppression to obtain phosphorylated pS76-NAGK, which was subsequently converted to site-specifically pyrophosphorylated NAGK (ppS76-NAGK) with a phosphorimidazolide reagent. A significant reduction in GlcNAc kinase activity was observed upon phosphorylation and near-complete inactivation upon pyrophosphorylation. The formation of ppS76-NAGK proceeded via an ATP-dependent autocatalytic process, and once formed, ppS76-NAGK displayed notable stability toward dephosphorylation in mammalian cell lysates. Proteomic examination unveiled a distinct set of protein-protein interactions for ppS76-NAGK, suggesting an alternative function, independent of its kinase activity. Overall, a significant regulatory role of pyrophosphorylation on NAGK activity was uncovered, providing a strong incentive to investigate the influence of this unusual phosphorylation mode on other kinases.
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Affiliation(s)
- Arif Celik
- Leibniz-Forschungsinstitut
für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany
- Institut
für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
| | - Ida Beyer
- Leibniz-Forschungsinstitut
für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany
| | - Dorothea Fiedler
- Leibniz-Forschungsinstitut
für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany
- Institut
für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
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14
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Ocius KL, Kolli SH, Ahmad SS, Dressler JM, Chordia MD, Jutras BL, Rutkowski MR, Pires MM. Noninvasive Analysis of Peptidoglycan from Living Animals. Bioconjug Chem 2024; 35:489-498. [PMID: 38591251 PMCID: PMC11036361 DOI: 10.1021/acs.bioconjchem.4c00007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 03/25/2024] [Accepted: 03/27/2024] [Indexed: 04/10/2024]
Abstract
The role of the intestinal microbiota in host health is increasingly revealed in its contributions to disease states. The host-microbiome interaction is multifactorial and dynamic. One of the factors that has recently been strongly associated with host physiological responses is peptidoglycan from bacterial cell walls. Peptidoglycan from gut commensal bacteria activates peptidoglycan sensors in human cells, including the nucleotide-binding oligomerization domain-containing protein 2. When present in the gastrointestinal tract, both the polymeric form (sacculi) and depolymerized fragments can modulate host physiology, including checkpoint anticancer therapy efficacy, body temperature and appetite, and postnatal growth. To utilize this growing area of biology toward therapeutic prescriptions, it will be critical to directly analyze a key feature of the host-microbiome interaction from living hosts in a reproducible and noninvasive way. Here we show that metabolically labeled peptidoglycan/sacculi can be readily isolated from fecal samples collected from both mice and humans. Analysis of fecal samples provided a noninvasive route to probe the gut commensal community including the metabolic synchronicity with the host circadian clock. Together, these results pave the way for noninvasive diagnostic tools to interrogate the causal nature of peptidoglycan in host health and disease.
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Affiliation(s)
- Karl L. Ocius
- Department
of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States
| | - Sree H. Kolli
- Department
of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22904, United States
| | - Saadman S. Ahmad
- Department
of Biochemistry, Virginia Tech, Blacksburg, Virginia 24061, United States
- Fralin
Life Sciences Institute, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Jules M. Dressler
- Department
of Biochemistry, Virginia Tech, Blacksburg, Virginia 24061, United States
- Fralin
Life Sciences Institute, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Mahendra D. Chordia
- Department
of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States
| | - Brandon L. Jutras
- Department
of Biochemistry, Virginia Tech, Blacksburg, Virginia 24061, United States
- Fralin
Life Sciences Institute, Virginia Tech, Blacksburg, Virginia 24061, United States
- Center
for Emerging, Zoonotic and Arthropod-borne Pathogens, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Melanie R. Rutkowski
- Department
of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22904, United States
| | - Marcos M. Pires
- Department
of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States
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15
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Sundaram B, Tweedell RE, Prasanth Kumar S, Kanneganti TD. The NLR family of innate immune and cell death sensors. Immunity 2024; 57:674-699. [PMID: 38599165 PMCID: PMC11112261 DOI: 10.1016/j.immuni.2024.03.012] [Citation(s) in RCA: 62] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/07/2024] [Accepted: 03/12/2024] [Indexed: 04/12/2024]
Abstract
Nucleotide-binding oligomerization domain (NOD)-like receptors, also known as nucleotide-binding leucine-rich repeat receptors (NLRs), are a family of cytosolic pattern recognition receptors that detect a wide variety of pathogenic and sterile triggers. Activation of specific NLRs initiates pro- or anti-inflammatory signaling cascades and the formation of inflammasomes-multi-protein complexes that induce caspase-1 activation to drive inflammatory cytokine maturation and lytic cell death, pyroptosis. Certain NLRs and inflammasomes act as integral components of larger cell death complexes-PANoptosomes-driving another form of lytic cell death, PANoptosis. Here, we review the current understanding of the evolution, structure, and function of NLRs in health and disease. We discuss the concept of NLR networks and their roles in driving cell death and immunity. An improved mechanistic understanding of NLRs may provide therapeutic strategies applicable across infectious and inflammatory diseases and in cancer.
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Affiliation(s)
- Balamurugan Sundaram
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Rebecca E Tweedell
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
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16
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Yuan Z, Ye J, Liu B, Zhang L. Unraveling the role of autophagy regulation in Crohn's disease: from genetic mechanisms to potential therapeutics. ADVANCED BIOTECHNOLOGY 2024; 2:14. [PMID: 39883213 PMCID: PMC11740883 DOI: 10.1007/s44307-024-00021-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 02/29/2024] [Accepted: 03/10/2024] [Indexed: 01/31/2025]
Abstract
Autophagy serves as the primary intracellular degradation mechanism in which damaged organelles and self-cytoplasmic proteins are transported to the lysosome for degradation. Crohn's disease, an idiopathic chronic inflammatory disorder of the gastrointestinal tract, manifests in diverse regions of the digestive system. Recent research suggests that autophagy modulation may be a new avenue for treating Crohn's disease, and several promising small-molecule modulators of autophagy have been reported as therapeutic options. In this review, we discuss in detail how mutations in autophagy-related genes function in Crohn's disease and summarize the modulatory effects on autophagy of small-molecule drugs currently used for Crohn's disease treatment. Furthermore, we delve into the therapeutic potential of small-molecule autophagy inducers on Crohn's disease, emphasizing the prospects for development in this field. We aim to highlight the significance of autophagy modulation in Crohn's disease, with the aspiration of contributing to the development of more efficacious treatments that can alleviate their suffering, and improve their quality of life.
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Affiliation(s)
- Ziyue Yuan
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China
| | - Jing Ye
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bo Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Lan Zhang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
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17
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Shi Y, Bashian EE, Hou Y, Wu P. Chemical immunology: Recent advances in tool development and applications. Cell Chem Biol 2024; 31:S2451-9456(24)00080-1. [PMID: 38508196 PMCID: PMC11393185 DOI: 10.1016/j.chembiol.2024.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 02/01/2024] [Accepted: 02/22/2024] [Indexed: 03/22/2024]
Abstract
Immunology was one of the first biological fields to embrace chemical approaches. The development of new chemical approaches and techniques has provided immunologists with an impressive arsenal of tools to address challenges once considered insurmountable. This review focuses on advances at the interface of chemistry and immunobiology over the past two decades that have not only opened new avenues in basic immunological research, but also revolutionized drug development for the treatment of cancer and autoimmune diseases. These include chemical approaches to understand and manipulate antigen presentation and the T cell priming process, to facilitate immune cell trafficking and regulate immune cell functions, and therapeutic applications of chemical approaches to disease control and treatment.
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Affiliation(s)
- Yujie Shi
- Department of Molecular and Cellular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Eleanor E Bashian
- Department of Molecular and Cellular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Yingqin Hou
- Department of Molecular and Cellular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Peng Wu
- Department of Molecular and Cellular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
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18
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Lee JS, Kim C. Role of CARD9 in Cell- and Organ-Specific Immune Responses in Various Infections. Int J Mol Sci 2024; 25:2598. [PMID: 38473845 DOI: 10.3390/ijms25052598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 02/20/2024] [Accepted: 02/21/2024] [Indexed: 03/14/2024] Open
Abstract
The caspase recruitment domain-containing protein 9 (CARD9) is an intracellular adaptor protein that is abundantly expressed in cells of the myeloid lineage, such as neutrophils, macrophages, and dendritic cells. CARD9 plays a critical role in host immunity against infections caused by fungi, bacteria, and viruses. A CARD9 deficiency impairs the production of inflammatory cytokines and chemokines as well as migration and infiltration, thereby increasing susceptibility to infections. However, CARD9 signaling varies depending on the pathogen causing the infection. Furthermore, different studies have reported altered CARD9-mediated signaling even with the same pathogen. Therefore, this review focuses on and elucidates the current literature on varied CARD9 signaling in response to various infectious stimuli in humans and experimental mice models.
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Affiliation(s)
- Ji Seok Lee
- Laboratory of Leukocyte Signaling Research, Department of Pharmacology, Inha University School of Medicine, Incheon 22212, Republic of Korea
- BK21, Program in Biomedical Science & Engineering, Inha University, Incheon 22212, Republic of Korea
| | - Chaekyun Kim
- Laboratory of Leukocyte Signaling Research, Department of Pharmacology, Inha University School of Medicine, Incheon 22212, Republic of Korea
- BK21, Program in Biomedical Science & Engineering, Inha University, Incheon 22212, Republic of Korea
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19
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Adamson C, Liang Y, Feng S, Ng AWR, Qiao Y. A closer look at ligand specificity for cellular activation of NOD2 with synthetic muramyl dipeptide analogues. Chem Commun (Camb) 2024; 60:2212-2215. [PMID: 38305731 DOI: 10.1039/d3cc05807g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
To further understand the specificity of muramyl dipeptide (MDP) sensing by NOD2, we evaluated the compatibility of synthetic MDP analogues for cellular uptake and NAGK phosphorylation, the pre-requisite steps of intracellular NOD2 activation. Our results revealed that these two prior steps do not confer ligand stereoselectivity; yet NAGK strictly discriminates against the disaccharide NOD2 agonists for phosphorylation in vitro, despite it being indispensable for the cellular NOD2-stimulating effects of these analogues, implying potential glycosidase cleavage as a novel intermediate step for cellular activation of NOD2.
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Affiliation(s)
- Christopher Adamson
- School of Chemistry, Chemical Engineering and Biotechnology (CCEB), Nanyang Technological University (NTU), 21 Nanyang Link, 637371, Singapore.
| | - Yaquan Liang
- School of Chemistry, Chemical Engineering and Biotechnology (CCEB), Nanyang Technological University (NTU), 21 Nanyang Link, 637371, Singapore.
| | - Shiliu Feng
- School of Chemistry, Chemical Engineering and Biotechnology (CCEB), Nanyang Technological University (NTU), 21 Nanyang Link, 637371, Singapore.
| | - Allan Wee Ren Ng
- School of Chemistry, Chemical Engineering and Biotechnology (CCEB), Nanyang Technological University (NTU), 21 Nanyang Link, 637371, Singapore.
| | - Yuan Qiao
- School of Chemistry, Chemical Engineering and Biotechnology (CCEB), Nanyang Technological University (NTU), 21 Nanyang Link, 637371, Singapore.
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20
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Wheeler R, Gomperts Boneca I. The hidden base of the iceberg: gut peptidoglycome dynamics is foundational to its influence on the host. Gut Microbes 2024; 16:2395099. [PMID: 39239828 PMCID: PMC11382707 DOI: 10.1080/19490976.2024.2395099] [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: 12/21/2023] [Revised: 07/01/2024] [Accepted: 08/16/2024] [Indexed: 09/07/2024] Open
Abstract
The intestinal microbiota of humans includes a highly diverse range of bacterial species. All these bacteria possess a cell wall, composed primarily of the macromolecule peptidoglycan. As such, the gut also harbors an abundant and varied peptidoglycome. A remarkable range of host physiological pathways are regulated by peptidoglycan fragments that originate from the gut microbiota and enter the host system. Interactions between the host system and peptidoglycan can influence physiological development and homeostasis, promote health, or contribute to inflammatory disease. Underlying these effects is the interplay between microbiota composition and enzymatic processes that shape the intestinal peptidoglycome, dictating the types of peptidoglycan generated, that subsequently cross the gut barrier. In this review, we highlight and discuss the hidden and emerging functional aspects of the microbiome, i.e. the hidden base of the iceberg, that modulate the composition of gut peptidoglycan, and how these fundamental processes are drivers of physiological outcomes for the host.
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Affiliation(s)
- Richard Wheeler
- Institut Pasteur, Université Paris Cité, Paris, France
- Hauts-de-Seine, Arthritis Research and Development, Neuilly-sur-Seine, France
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21
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Greenblatt CL, Lathe R. Vaccines and Dementia: Part I. Non-Specific Immune Boosting with BCG: History, Ligands, and Receptors. J Alzheimers Dis 2024; 98:343-360. [PMID: 38393912 PMCID: PMC10977417 DOI: 10.3233/jad-231315] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/15/2024] [Indexed: 02/25/2024]
Abstract
Vaccines such as Bacille Calmette-Guérin (BCG) can apparently defer dementia onset with an efficacy better than all drugs known to date, as initially reported by Gofrit et al. (PLoS One14, e0224433), now confirmed by other studies. Understanding how and why is of immense importance because it could represent a sea-change in how we manage patients with mild cognitive impairment through to dementia. Given that infection and/or inflammation are likely to contribute to the development of dementias such as Alzheimer's disease (Part II of this work), we provide a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents. We review early studies in which poxvirus, herpes virus, and tuberculosis (TB) infections afford cross-protection against unrelated pathogens, a concept known as 'trained immunity'. We then focus on the attenuated TB vaccine, BCG, that was introduced to protect against the causative agent of TB, Mycobacterium tuberculosis. We trace the development of BCG in the 1920 s through to the discovery, by Freund and McDermott in the 1940 s, that extracts of mycobacteria can themselves exert potent immunostimulating (adjuvant) activity; Freund's complete adjuvant based on mycobacteria remains the most potent immunopotentiator reported to date. We then discuss whether the beneficial effects of BCG require long-term persistence of live bacteria, before focusing on the specific mycobacterial molecules, notably muramyl dipeptides, that mediate immunopotentiation, as well as the receptors involved. Part II addresses evidence that immunopotentiation by BCG and other vaccines can protect against dementia development.
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Affiliation(s)
- Charles L. Greenblatt
- Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel–Canada (IMRIC), Hebrew University of Jerusalem, Jerusalem, Israel
| | - Richard Lathe
- Division of Infection Medicine, University of Edinburgh Medical School, Edinburgh, UK
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22
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Kim D, Choi H, Oh H, Lee J, Hwang Y, Kang SS. Mutanolysin-Digested Peptidoglycan of Lactobacillus reuteri Promotes the Inhibition of Porphyromonas gingivalis Lipopolysaccharide-Induced Inflammatory Responses through the Regulation of Signaling Cascades via TLR4 Suppression. Int J Mol Sci 2023; 25:42. [PMID: 38203215 PMCID: PMC10779245 DOI: 10.3390/ijms25010042] [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: 11/01/2023] [Revised: 12/08/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open
Abstract
Periodontitis is an oral infectious disease caused by various pathogenic bacteria, such as Porphyromonas gingivalis. Although probiotics and their cellular components have demonstrated positive effects on periodontitis, the beneficial impact of peptidoglycan (PGN) from probiotic Lactobacillus remains unclear. Therefore, our study sought to investigate the inhibitory effect of PGN isolated from L. reuteri (LrPGN) on P. gingivalis-induced inflammatory responses. Pretreatment with LrPGN significantly inhibited the production of interleukin (IL)-1β, IL-6, and CCL20 in RAW 264.7 cells induced by P. gingivalis lipopolysaccharide (LPS). LrPGN reduced the phosphorylation of PI3K/Akt and MAPKs, as well as NF-κB activation, which were induced by P. gingivalis LPS. Furthermore, LrPGN dose-dependently reduced the expression of Toll-like receptor 4 (TLR4), indicating that LrPGN inhibits periodontal inflammation by regulating cellular signaling cascades through TLR4 suppression. Notably, LrPGN exhibited stronger inhibition of P. gingivalis LPS-induced production of inflammatory mediators compared to insoluble LrPGN and proteinase K-treated LrPGN. Moreover, MDP, a minimal bioactive PGN motif, also dose-dependently inhibited P. gingivalis LPS-induced inflammatory mediators, suggesting that MDP-like molecules present in the LrPGN structure may play a crucial role in the inhibition of inflammatory responses. Collectively, these findings suggest that LrPGN can mitigate periodontal inflammation and could be a useful agent for the prevention and treatment of periodontitis.
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Affiliation(s)
- Donghan Kim
- Department of Food Science and Biotechnology, College of Life Science and Biotechnology, Dongguk University, Goyang 10326, Republic of Korea
| | - Hanhee Choi
- Department of Food Science and Biotechnology, College of Life Science and Biotechnology, Dongguk University, Goyang 10326, Republic of Korea
| | - Hyeonjun Oh
- Department of Food Science and Biotechnology, College of Life Science and Biotechnology, Dongguk University, Goyang 10326, Republic of Korea
| | - Jiyeon Lee
- Department of Food Science and Biotechnology, College of Life Science and Biotechnology, Dongguk University, Goyang 10326, Republic of Korea
| | - Yongjin Hwang
- Novalacto Co., Ltd., Daejon 34016, Republic of Korea
| | - Seok-Seong Kang
- Department of Food Science and Biotechnology, College of Life Science and Biotechnology, Dongguk University, Goyang 10326, Republic of Korea
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23
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Tsukidate T, Hespen CW, Hang HC. Small molecule modulators of immune pattern recognition receptors. RSC Chem Biol 2023; 4:1014-1036. [PMID: 38033733 PMCID: PMC10685800 DOI: 10.1039/d3cb00096f] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 10/03/2023] [Indexed: 12/02/2023] Open
Abstract
Pattern recognition receptors (PRRs) represent a re-emerging class of therapeutic targets for vaccine adjuvants, inflammatory diseases and cancer. In this review article, we summarize exciting developments in discovery and characterization of small molecule PRR modulators, focusing on Toll-like receptors (TLRs), NOD-like receptors (NLRs) and the cGAS-STING pathway. We also highlight PRRs that are currently lacking small molecule modulators and opportunities for chemical biology and therapeutic discovery.
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Affiliation(s)
- Taku Tsukidate
- Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York New York 10065 USA
| | - Charles W Hespen
- Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York New York 10065 USA
| | - Howard C Hang
- Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York New York 10065 USA
- Department of Immunology and Microbiology and Department of Chemistry, Scripps Research, La Jolla California 92037 USA
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24
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Ocius KL, Kolli SH, Ahmad SS, Dressler JM, Chordia MD, Jutras BL, Rutkowski MR, Pires MM. Non-invasive Analysis of Peptidoglycan from Living Animals. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.21.549941. [PMID: 37693563 PMCID: PMC10491127 DOI: 10.1101/2023.07.21.549941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
The role of the intestinal microbiota in host health is increasingly revealed in its contributions to disease states. The host-microbiome interaction is multifactorial and dynamic. One of the factors that has recently been strongly associated with host physiological responses is peptidoglycan from bacterial cell walls. Peptidoglycan from gut commensal bacteria activate peptidoglycan sensors in human cells, including the Nucleotide-binding oligomerization domain containing protein 2 (NOD2). When present in the gastrointestinal tract, both the polymeric form (sacculi) and de-polymerized fragments can modulate host physiology, including checkpoint anticancer therapy efficacy, body temperature and appetite, and postnatal growth. To leverage this growing area of biology towards therapeutic prescriptions, it will be critical to directly analyze a key feature of the host-microbiome interaction from living hosts in a reproducible and non-invasive way. Here we show that metabolically labeled peptidoglycan/sacculi can be readily isolated from fecal samples collected from both mice and humans. Analysis of fecal samples provided a non-invasive route to probe the gut commensal community including the metabolic synchronicity with the host circadian clock. Together, these results pave the way for non-invasive diagnostic tools to interrogate the causal nature of peptidoglycan in host health and disease.
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25
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Richard N, Savoye G, Leboutte M, Amamou A, Ghosh S, Marion-Letellier R. Crohn’s disease: Why the ileum? World J Gastroenterol 2023; 29:3222-3240. [PMID: 37377591 PMCID: PMC10292140 DOI: 10.3748/wjg.v29.i21.3222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 05/08/2023] [Indexed: 06/01/2023] Open
Abstract
Crohn’s disease (CD) is an inflammatory bowel disease characterized by immune-mediated flares affecting any region of the intestine alternating with remission periods. In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type. Moreover, the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes. Most of these genes are associated with Paneth cell dysfunction, a cell type found in the intestinal crypts of the ileum. Besides, a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota, which in turn modulates the susceptibility of the ileum to inflammation. Thus, the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis. Indeed, both immune response and cellular healing processes harbour differences between ileal and non-ileal CD. Taken together, these findings advocate for a dedicated therapeutic approach to managing ileal CD. Currently, interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site. However, the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.
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Affiliation(s)
- Nicolas Richard
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Guillaume Savoye
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Mathilde Leboutte
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Asma Amamou
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Subrata Ghosh
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Rachel Marion-Letellier
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
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26
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Le HT, Liu M, Grimes CL. Application of bioanalytical and computational methods in decoding the roles of glycans in host-pathogen interactions. Curr Opin Chem Biol 2023; 74:102301. [PMID: 37080155 PMCID: PMC10296625 DOI: 10.1016/j.cbpa.2023.102301] [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: 12/05/2022] [Revised: 03/09/2023] [Accepted: 03/14/2023] [Indexed: 04/22/2023]
Abstract
Host-pathogen interactions (HPIs) are complex processes that require tight regulation. A common regulatory mechanism of HPIs is through glycans of either host cells or pathogens. Due to their diverse sequences, complex structures, and conformations, studies of glycans require highly sensitive and powerful tools. Recent improvements in technology have enabled the application of many bioanalytical techniques and modeling methods to investigate glycans and their mechanisms in HPIs. This mini-review highlights how these advances have been used to understand the role glycans play in HPIs in the past 2 years.
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Affiliation(s)
- Ha T Le
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Min Liu
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Catherine L Grimes
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA; Department of Biological Sciences, University of Delaware, Newark, DE, USA.
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27
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Abstract
Mycobacteria are responsible for several human and animal diseases. NOD2 is a pattern recognition receptor that has an important role in mycobacterial recognition. However, the mechanisms by which mutations in NOD2 alter the course of mycobacterial infection remain unclear. Herein, we aimed to review the totality of studies directly addressing the relationship between NOD2 and mycobacteria as a foundation for moving the field forward. NOD2 was linked to mycobacterial infection at 3 levels: (1) genetic, through association with mycobacterial diseases of humans; (2) chemical, through the distinct NOD2 ligand in the mycobacterial cell wall; and (3) immunologic, through heightened NOD2 signaling caused by the unique modification of the NOD2 ligand. The immune response to mycobacteria is shaped by NOD2 signaling, responsible for NF-κB and MAPK activation, and the production of various immune effectors like cytokines and nitric oxide, with some evidence linking this to bacteriologic control. Absence of NOD2 during mycobacterial infection of mice can be detrimental, but the mechanism remains unknown. Conversely, the success of immunization with mycobacteria has been linked to NOD2 signaling and NOD2 has been targeted as an avenue of immunotherapy for diseases even beyond mycobacteria. The mycobacteria-NOD2 interaction remains an important area of study, which may shed light on immune mechanisms in disease.
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Affiliation(s)
- Jean-Yves Dubé
- Department of Microbiology and Immunology, McGill University, Montréal, Canada
| | - Marcel A. Behr
- Department of Medicine, McGill University Health Centre, Montréal, Canada
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28
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Chiok KR, Dhar N, Banerjee A. Mycobacterium tuberculosis and SARS-CoV-2 co-infections: The knowns and unknowns. iScience 2023; 26:106629. [PMID: 37091987 PMCID: PMC10082467 DOI: 10.1016/j.isci.2023.106629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023] Open
Abstract
Health impacts of Mycobacterium tuberculosis (Mtb) and SARS-CoV-2 co-infections are not fully understood. Both pathogens modulate host responses and induce immunopathology with extensive lung damage. With a quarter of the world's population harboring latent TB, exploring the relationship between SARS-CoV-2 infection and its effect on the transition of Mtb from latent to active form is paramount to control this pathogen. The effects of active Mtb infection on establishment and severity of COVID-19 are also unknown, despite the ability of TB to orchestrate profound long-lasting immunopathologies in the lungs. Absence of mechanistic studies and co-infection models hinder the development of effective interventions to reduce the health impacts of SARS-CoV-2 and Mtb co-infection. Here, we highlight dysregulated immune responses induced by SARS-CoV-2 and Mtb, their potential interplay, and implications for co-infection in the lungs. As both pathogens master immunomodulation, we discuss relevant converging and diverging immune-related pathways underlying SARS-CoV-2 and Mtb co-infections.
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Affiliation(s)
- Kim R Chiok
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada
| | - Neeraj Dhar
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
- Respiratory Research Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - Arinjay Banerjee
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada
- Respiratory Research Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
- Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada
- Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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29
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Kwan JMC, Qiao Y. Mechanistic Insights into the Activities of Major Families of Enzymes in Bacterial Peptidoglycan Assembly and Breakdown. Chembiochem 2023; 24:e202200693. [PMID: 36715567 DOI: 10.1002/cbic.202200693] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/28/2023] [Accepted: 01/30/2023] [Indexed: 01/31/2023]
Abstract
Serving as an exoskeletal scaffold, peptidoglycan is a polymeric macromolecule that is essential and conserved across all bacteria, yet is absent in mammalian cells; this has made bacterial peptidoglycan a well-established excellent antibiotic target. In addition, soluble peptidoglycan fragments derived from bacteria are increasingly recognised as key signalling molecules in mediating diverse intra- and inter-species communication in nature, including in gut microbiota-host crosstalk. Each bacterial species encodes multiple redundant enzymes for key enzymatic activities involved in peptidoglycan assembly and breakdown. In this review, we discuss recent findings on the biochemical activities of major peptidoglycan enzymes, including peptidoglycan glycosyltransferases (PGT) and transpeptidases (TPs) in the final stage of peptidoglycan assembly, as well as peptidoglycan glycosidases, lytic transglycosylase (LTs), amidases, endopeptidases (EPs) and carboxypeptidases (CPs) in peptidoglycan turnover and metabolism. Biochemical characterisation of these enzymes provides valuable insights into their substrate specificity, regulation mechanisms and potential modes of inhibition.
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Affiliation(s)
- Jeric Mun Chung Kwan
- School of Chemistry, Chemical Engineering and Biotechnology (CCEB), 21 Nanyang Link, Singapore, 637371, Singapore.,LKC School of Medicine, Nanyang Technological University (NTU) Singapore, 11 Mandalay Road, Singapore, Singapore, 208232, Singapore
| | - Yuan Qiao
- School of Chemistry, Chemical Engineering and Biotechnology (CCEB), Nanyang Technological University (NTU), Singapore, 21 Nanyang Link, Singapore, 637371, Singapore
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30
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Pham AT, Ghilardi AF, Sun L. Recent advances in the development of RIPK2 modulators for the treatment of inflammatory diseases. Front Pharmacol 2023; 14:1127722. [PMID: 36959850 PMCID: PMC10028200 DOI: 10.3389/fphar.2023.1127722] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/21/2023] [Indexed: 03/09/2023] Open
Abstract
Receptor-interacting serine/threonine kinase 2 (RIPK2) is a vital immunomodulator that plays critical roles in nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs) signaling. Stimulated NOD1 and NOD2 interact with RIPK2 and lead to the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK), followed by the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12/23. Defects in NOD/RIPK2 signaling are associated with numerous inflammatory diseases, including asthma, sarcoidosis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), multiple sclerosis, and Blau syndrome. As RIPK2 is a crucial element of innate immunity, small molecules regulating RIPK2 functions are attractive to establish novel immunotherapies. The increased interest in developing RIPK2 inhibitors has led to the clinical investigations of novel drug candidates. In this review, we attempt to summarize recent advances in the development of RIPK2 inhibitors and degraders.
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31
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Zhao X, Yang X, Hang HC. Chemoproteomic Analysis of Microbiota Metabolite-Protein Targets and Mechanisms. Biochemistry 2022; 61:2822-2834. [PMID: 34989554 PMCID: PMC9256862 DOI: 10.1021/acs.biochem.1c00758] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The microbiota have emerged as an important factor in host physiology, disease, and response to therapy. These diverse microbes (bacteria, virus, fungi, and protists) encode unique functions and metabolites that regulate intraspecies and interspecies interactions. While the mechanisms of some microbiota species and metabolites have been elucidated, the diversity and abundance of different microbiota species and their associated pathways suggest many more metabolites and mechanisms of action remain to be discovered. In this Perspective, we highlight how the advances in chemical proteomics have provided new opportunities to elucidate the molecular targets of specific microbiota metabolites and reveal new mechanisms of action. The continued development of specific microbiota metabolite reporters and more precise proteomic methods should reveal new microbiota mechanisms of action, therapeutic targets, and biomarkers for a variety of human diseases.
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32
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Li J, Liu S, Zhang Y, Huang Q, Zhang H, OuYang J, Mao F, Fan H, Yi W, Dong M, Xu A, Huang S. Two novel mollusk short-form ApeC-containing proteins act as pattern recognition proteins for peptidoglycan. Front Immunol 2022; 13:971883. [PMID: 36275759 PMCID: PMC9585378 DOI: 10.3389/fimmu.2022.971883] [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: 06/17/2022] [Accepted: 09/08/2022] [Indexed: 11/18/2022] Open
Abstract
The Apextrin C-terminal (ApeC) domain is a new protein domain largely specific to aquatic invertebrates. In amphioxus, a short-form ApeC-containing protein (ACP) family is capable of binding peptidoglycan (PGN) and agglutinating bacteria via its ApeC domain. However, the functions of ApeC in other phyla remain unknown. Here we examined 130 ACPs from gastropods and bivalves, the first and second biggest mollusk classes. They were classified into nine groups based on their phylogenetics and architectures, including three groups of short-form ACPs, one group of apextrins and two groups of ACPs of complex architectures. No groups have orthologs in other phyla and only four groups have members in both gastropods and bivalves, suggesting that mollusk ACPs are highly diversified. We selected one bivalve ACP (CgACP1; from the oyster Crossostrea gigas) and one gastropod ACP (BgACP1; from the snail Biomphalaria glabrata) for functional experiments. Both are highly-expressed, secreted short-form ACPs and hence comparable to the amphioxus ACPs previously reported. We found that recombinant CgACP1 and BgACP1 bound with yeasts and several bacteria with different affinities. They also agglutinated these microbes, but showed no inhibiting or killing effects. Further analyses show that both ACPs had high affinities to the Lys-type PGN from S. aureus but weak or no affinities to the DAP-type PGN from Bacillus subtilis. Both recombinant ACPs displayed weak or no affinities to other microbial cell wall components, including lipopolysaccharide (LPS), lipoteichoic acid (LTA), zymosan A, chitin, chitosan and cellulose, as well as to several PGN moieties, including muramyl dipeptide (MDP), N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc). Besides, CgACP1 had the highest expression in the gill and could be greatly up-regulated quickly after bacterial challenge. This is reminiscent of the amphioxus ACP1/2 which serve as essential mucus lectins in the gill. Taken together, the current findings from mollusk and amphioxus ACPs suggest several basic common traits for the ApeC domains, including the high affinity to Lys-type PGN, the bacterial binding and agglutinating capacity, and the role as mucus proteins to protect the mucosal surface.
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Affiliation(s)
- Jin Li
- Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Shumin Liu
- Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Yang Zhang
- Chinese Academy of Sciences Key Laboratory of Tropical Marine Bio-Resources and Ecology and Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China
| | - Qiuyun Huang
- Chinese Academy of Sciences Key Laboratory of Tropical Marine Bio-Resources and Ecology and Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China
| | - Hao Zhang
- Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Jihua OuYang
- Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Fan Mao
- Chinese Academy of Sciences Key Laboratory of Tropical Marine Bio-Resources and Ecology and Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China
| | - Huiping Fan
- Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Wenjie Yi
- Chinese Academy of Sciences Key Laboratory of Tropical Marine Bio-Resources and Ecology and Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China
| | - Meiling Dong
- Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Anlong Xu
- Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Shengfeng Huang
- Key Laboratory of Biocontrol, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
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33
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Godkowicz M, Druszczyńska M. NOD1, NOD2, and NLRC5 Receptors in Antiviral and Antimycobacterial Immunity. Vaccines (Basel) 2022; 10:vaccines10091487. [PMID: 36146565 PMCID: PMC9503463 DOI: 10.3390/vaccines10091487] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/24/2022] Open
Abstract
The innate immune system recognizes pathogen-associated molecular motifs through pattern recognition receptors (PRRs) that induce inflammasome assembly in macrophages and trigger signal transduction pathways, thereby leading to the transcription of inflammatory cytokine genes. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) represent a family of cytosolic PRRs involved in the detection of intracellular pathogens such as mycobacteria or viruses. In this review, we discuss the role of NOD1, NOD2, and NLRC5 receptors in regulating antiviral and antimycobacterial immune responses by providing insight into molecular mechanisms as well as their potential health and disease implications.
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Affiliation(s)
- Magdalena Godkowicz
- Lodz Institutes of the Polish Academy of Sciences, The Bio-Med-Chem Doctoral School, University of Lodz, 90-237 Lodz, Poland
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha12/16, 90-237 Lodz, Poland
- Correspondence:
| | - Magdalena Druszczyńska
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha12/16, 90-237 Lodz, Poland
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34
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Vacariu CM, Tanner ME. Recent Advances in the Synthesis and Biological Applications of Peptidoglycan Fragments. Chemistry 2022; 28:e202200788. [PMID: 35560956 DOI: 10.1002/chem.202200788] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Indexed: 11/09/2022]
Abstract
The biosynthesis, breakdown, and modification of peptidoglycan (PG) play vital roles in both bacterial viability and in the response of human physiology to bacterial infection. Studies on PG biochemistry are hampered by the fact that PG is an inhomogeneous insoluble macromolecule. Chemical synthesis is therefore an important means to obtain PG fragments that may serve as enzyme substrates and elicitors of the human immune response. This review outlines the recent advances in the synthesis and biochemical studies of PG fragments, PG biosynthetic intermediates (such as Park's nucleotides and PG lipids), and PG breakdown products (such as muramyl dipeptides and anhydro-muramic acid-containing fragments). A rich variety of synthetic approaches has been applied to preparing such compounds since carbohydrate, peptide, and phospholipid chemical methodologies must all be applied.
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Affiliation(s)
- Condurache M Vacariu
- Department of Chemistry, University of British Columbia, V6T 1Z1, Vancouver, British Columbia, Canada
| | - Martin E Tanner
- Department of Chemistry, University of British Columbia, V6T 1Z1, Vancouver, British Columbia, Canada
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35
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Abstract
The microbiome modulates brain function, but the precise routes of gut-brain communication remain unclear. In a recent issue of Science, Gabanyi et al. discover that hypothalamic GABAergic neurons directly recognize microbial muropeptides via NOD2, leading to reduced neuronal activity, loss of appetite, and aberrant thermoregulation.
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36
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Dubé JY, McIntosh F, Behr MA. Mice Dually Disrupted for Nod2 and Mincle Manifest Early Bacteriological Control but Late Susceptibility During Mycobacterium tuberculosis Infection. Front Immunol 2022; 13:862992. [PMID: 35418999 PMCID: PMC8995500 DOI: 10.3389/fimmu.2022.862992] [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: 01/26/2022] [Accepted: 03/04/2022] [Indexed: 11/13/2022] Open
Abstract
Pattern recognition receptors Mincle and NOD2 have been implicated in mycobacterial immunity. However, knockout (KO) animal infection studies with Mycobacterium tuberculosis (Mtb) have had mild/delayed phenotypes. Given that genetic susceptibility to infectious diseases can be polygenic, we hypothesized that murine double knockout (DKO) of Mincle and Nod2 would result in exacerbation of altered immunity to mycobacterial infection leading to a more extreme phenotype than either KO alone. To test this hypothesis, we monitored bacterial burden, immune responses and survival following in vivo infections with Mtb in DKO mice for comparison to wildtype (WT) and single KOs. Bacterial burden and immune responses were not significantly affected at 3 and 6 weeks after infection in all mutant mice. At later timepoints, Nod2-KO mice had reduced survival compared to wildtype mice, and Mincle-KO survival was intermediate. Unexpectedly, dual disruption had no further effect; rather, DKO mice phenocopied Nod2-KO mice. We observed that Mtb-related death, exclusively in mice with disrupted Nod2, was accompanied by greater pulmonary cell death and distinct large necrotic foci. Therefore, determining how these receptors contribute to mycobacterial resistance will require analysis of immunophenotypes and their consequences on host pathology.
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Affiliation(s)
- Jean-Yves Dubé
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada.,Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada.,McGill International TB Centre, Montréal, QC, Canada
| | - Fiona McIntosh
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada.,McGill International TB Centre, Montréal, QC, Canada
| | - Marcel A Behr
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada.,Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada.,McGill International TB Centre, Montréal, QC, Canada.,Department of Medicine, McGill University Health Centre, Montréal, QC, Canada
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37
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Prati C, Pilar EFS, Cartel A, Pitoni JBG, Vasconcellos C, Costa AD. Dietary supplementation with gamma-linolenic, linoleic and oleic acids decreases PPAR-gamma expression and helps the tetracycline derivative to reduce NOD2 expression in patients with acne vulgaris. An Bras Dermatol 2022; 97:253-257. [PMID: 35058078 PMCID: PMC9073290 DOI: 10.1016/j.abd.2020.11.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/14/2020] [Indexed: 11/01/2022] Open
Affiliation(s)
- Clarissa Prati
- Instituto de Assistência Médica ao Servidor Público Estadual, São Paulo, SP, Brazil.
| | | | - Andre Cartel
- Hospital de Clínicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | | | - Cidia Vasconcellos
- Instituto de Assistência Médica ao Servidor Público Estadual, São Paulo, SP, Brazil
| | - Adilson da Costa
- Instituto de Assistência Médica ao Servidor Público Estadual, São Paulo, SP, Brazil.
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38
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Pei G. Identification of Novel Endogenous NOD Ligands: Quantitative Analysis of Binding Affinities of NOD1 or NOD2 with Sphingosine-1-Phosphate Using Microscale Thermophoresis. Methods Mol Biol 2022; 2523:151-160. [PMID: 35759196 DOI: 10.1007/978-1-0716-2449-4_10] [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] [Indexed: 06/15/2023]
Abstract
Nucleotide binding oligomerization domain-containing protein 1 (NOD1) and NOD2 have been identified as intracellular receptors for bacterial peptidoglycan for almost two decades; however, the direct binding with their respective ligands has only been recently demonstrated due to the difficulty of achieving large quantity of proteins with high purity. Here we describe a strategy combining immunoprecipitation of GFP-tagged proteins and microscale thermophoresis (MST) for efficient one-step purification of NOD1-GFP and NOD2-GFP and easy measurement of the binding affinities of NOD1 or NOD2 with sphingosine-1-phosphate (S1P) using small amount of proteins (nM range). This method will allow the identification of novel agonists/antagonists for NOD1/2.
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Affiliation(s)
- Gang Pei
- Institute for Immunology, Friedrich-Loeffler-Institut, Greifswald - Insel Riems, Germany.
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39
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Role of NR4A family members in myeloid cells and leukemia. CURRENT RESEARCH IN IMMUNOLOGY 2022; 3:23-36. [PMID: 35496823 PMCID: PMC9040138 DOI: 10.1016/j.crimmu.2022.02.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 02/01/2022] [Accepted: 02/10/2022] [Indexed: 11/24/2022] Open
Abstract
The myeloid cellular compartment comprises monocytes, dendritic cells (DCs), macrophages and granulocytes. As diverse as this group of cells may be, they are all an important part of the innate immune system and are therefore linked by the necessity to be acutely sensitive to their environment and to rapidly and appropriately respond to any changes that may occur. The nuclear orphan receptors NR4A1, NR4A2 and NR4A3 are encoded by immediate early genes as their expression is rapidly induced in response to various signals. It is perhaps because of this characteristic that this family of transcription factors has many known roles in myeloid cells. In this review, we will regroup and discuss the diverse roles NR4As have in different myeloid cell subsets, including in differentiation, migration, activation, and metabolism. We will also highlight the importance these molecules have in the development of myeloid leukemia.
NR4A1-3 have important roles in the different cells of the myeloid compartment. These orphan receptors homeostasis, differentiation, and activation. NR4A family is important in suppressing the development of myeloid leukemias. NR4As have been linked to several diseases and could be pharmacological targets.
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40
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Le HT, D’Ambrosio EA, Mashayekh S, Grimes CL. Customized peptidoglycan surfaces to investigate innate immune recognition via surface plasmon resonance. Methods Enzymol 2022; 665:73-103. [PMID: 35379444 PMCID: PMC9042648 DOI: 10.1016/bs.mie.2021.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Glycan-protein interactions facilitate some of the most important biomolecular processes in and between cells. They are involved in different cellular pathways, cell-cell interactions and associated with many diseases, making these interactions of great interest. However, their structural and functional diversity poses great challenges in studying them at the molecular level. Surface plasmon resonance (SPR) technology presents great advantages to study glycan-protein interactions due to its superior sensitivity, ability to monitor real-time interactions, relatively simple data interpretation, and most importantly, direct measurement of binding without a need for fluorescent labeling. Here, another dimensionality of SPR in studying glycan-protein interactions is demonstrated via examples of binding between human innate immune receptors and their bacterial peptidoglycan ligands. In order to best resemble interactions in solution, a novel strategy of tethering the carbohydrate at different positions to the biosensor surface is applied to represent the potential displays of the carbohydrate ligand to the receptor. Subsequent kinetic analysis provides insights into the optimized configuration of peptidoglycan fragments for binding with its receptors. The manuscript contains a "how-to guide" to help with the implementation of these methods in other glycan-protein binding systems.
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Affiliation(s)
- Ha T. Le
- Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
| | - Elizabeth A. D’Ambrosio
- Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
| | - Siavash Mashayekh
- Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
| | - Catherine Leimkuhler Grimes
- Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States,Department of Biological Sciences, University of Delaware, Newark, Delaware 19716, United States,Correspondence to Catherine L. Grimes, The University of Delaware, Department of Chemistry and Biochemistry, Newark, DE 19716,
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41
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Khan F, Khanam R, Wasim Qasim M, Wang Y, Jiang Z. Improved Synthesis of D‐Isoglutamine: Rapid Access to Desmuramyl Analogues of Muramyl Dipeptide for the Activation of Intracellular NOD2 Receptor and Vaccine Adjuvant Applications. European J Org Chem 2021. [DOI: 10.1002/ejoc.202101170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Farooq‐Ahmad Khan
- Third World Center (TWC) for Chemical Sciences International Center for Chemical & Biological Sciences University of Karachi-75270 Pakistan
- H.E.J. Research Institute of Chemistry International Center for Chemical & Biological Sciences University of Karachi-75270 Pakistan
| | - Rahila Khanam
- Third World Center (TWC) for Chemical Sciences International Center for Chemical & Biological Sciences University of Karachi-75270 Pakistan
- H.E.J. Research Institute of Chemistry International Center for Chemical & Biological Sciences University of Karachi-75270 Pakistan
| | - Muhammad Wasim Qasim
- Third World Center (TWC) for Chemical Sciences International Center for Chemical & Biological Sciences University of Karachi-75270 Pakistan
- H.E.J. Research Institute of Chemistry International Center for Chemical & Biological Sciences University of Karachi-75270 Pakistan
| | - Yan Wang
- H.E.J. Research Institute of Chemistry International Center for Chemical & Biological Sciences University of Karachi-75270 Pakistan
| | - Zi‐Hua Jiang
- Department of Chemistry Lakehead University 955 Oliver Rd Thunder Bay Ontario P7B 5E1 Canada
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42
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Maharana J, Maharana D, Bej A, Sahoo BR, Panda D, Wadavrao SB, Vats A, Pradhan SK, De S. Structural Elucidation of Inter-CARD Interfaces involved in NOD2 Tandem CARD Association and RIP2 Recognition. J Phys Chem B 2021; 125:13349-13365. [PMID: 34860029 DOI: 10.1021/acs.jpcb.1c06176] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Nucleotide-binding and oligomerization domain-containing protein 2 (NOD2) recognizes the muramyl dipeptide and activates the NF-κB signaling cascade following its interaction with receptor-interacting protein 2 (RIP2) via caspase recruitment domains (CARDs). The NOD2-RIP2 interaction is not understood well due to inadequate structural information. Using comparative modeling and multimicrosecond timescale molecular dynamics simulations, we have demonstrated the association of NOD2-CARDs (CARDa-CARDb) and their interaction with RIP2CARD. Our results suggest that a negatively charged interface of NOD2CARDa and positively charged type-Ia interface of NOD2CARDb are crucial for CARDa-CARDb association and the type-Ia interface of NOD2CARDa and type-Ib interface of RIP2CARD predicted to be involved in 1:1 CARD-CARD interaction. Moreover, the direct interaction of NOD2CARDb with RIP2CARD signifies the importance of both CARDs of NOD2 in RIP2-mediated CARD-CARD interaction. Altogether, the structural results could help in understanding the underlying molecular details of the NOD2-RIP2 association in higher and lower eukaryotes.
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Affiliation(s)
- Jitendra Maharana
- Department of Bioinformatics, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha 751001, India
| | - Diptimayee Maharana
- AEBN Division, ICAR-Central Inland Fisheries Research Institute, Barrackpore, West Bengal 700120, India
| | - Aritra Bej
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, West Bengal 700032, India
| | - Bikash R Sahoo
- Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Debashis Panda
- DBT-APSCS&T, Centre of Excellence for Bioresources and Sustainable Development, Kimin, Arunachal Pradesh 791121, India
| | - Sachin B Wadavrao
- OBC Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Telangana 500007, India
| | - Ashutosh Vats
- Animal Genomics Lab., Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, Haryana 132001, India
| | - Sukanta K Pradhan
- Department of Bioinformatics, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha 751001, India
| | - Sachinandan De
- Animal Genomics Lab., Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, Haryana 132001, India
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43
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Maršavelski A, Paurević M, Ribić R. Mannosylated adamantane-containing desmuramyl peptide recognition by the NOD2 receptor: a molecular dynamics study. Org Biomol Chem 2021; 19:7001-7012. [PMID: 34095941 DOI: 10.1039/d1ob00679g] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular receptor that recognizes the bacterial peptidoglycan fragment muramyl dipeptide (MDP). Our group has synthesized and biologically evaluated desmuramyl peptides containing adamantane and its mannose derivatives. The most active mannosylated derivative, ManAdDMP (Man-OCH2-d-(1-Ad)Gly-l-Ala-d-isoGln), is further characterized in silico in this study. We built intact model structures of the rabbit NOD2 protein, whose crystal structure lacks seven loops, and explored the binding of ManAdDMP. Two main binding sites for ManAdDMP are located within the nucleotide-binding oligomerization domain (NOD) and C-terminal leucine-rich repeat (LRR) domains. Our analysis shows that the dipeptide isoGln moiety of ManAdDMP significantly contributes to the binding, whereas the mannose moiety interacts with modelled loop 7, which is a part of the NOD helical domain 2. The presented results point to the importance of loops 2 and 7 in ligand recognition that could be useful for further investigation of NOD2 activation/inhibition.
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Affiliation(s)
- Aleksandra Maršavelski
- Department of Chemistry, Faculty of Science, University of Zagreb, HR-10000 Zagreb, Croatia.
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44
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Bastos PAD, Wheeler R, Boneca IG. Uptake, recognition and responses to peptidoglycan in the mammalian host. FEMS Microbiol Rev 2021; 45:5902851. [PMID: 32897324 PMCID: PMC7794044 DOI: 10.1093/femsre/fuaa044] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 09/03/2020] [Indexed: 12/13/2022] Open
Abstract
Microbiota, and the plethora of signalling molecules that they generate, are a major driving force that underlies a striking range of inter-individual physioanatomic and behavioural consequences for the host organism. Among the bacterial effectors, one finds peptidoglycan, the major constituent of the bacterial cell surface. In the steady-state, fragments of peptidoglycan are constitutively liberated from bacterial members of the gut microbiota, cross the gut epithelial barrier and enter the host system. The fate of these peptidoglycan fragments, and the outcome for the host, depends on the molecular nature of the peptidoglycan, as well the cellular profile of the recipient tissue, mechanism of cell entry, the expression of specific processing and recognition mechanisms by the cell, and the local immune context. At the target level, physiological processes modulated by peptidoglycan are extremely diverse, ranging from immune activation to small molecule metabolism, autophagy and apoptosis. In this review, we bring together a fragmented body of literature on the kinetics and dynamics of peptidoglycan interactions with the mammalian host, explaining how peptidoglycan functions as a signalling molecule in the host under physiological conditions, how it disseminates within the host, and the cellular responses to peptidoglycan.
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Affiliation(s)
- Paulo A D Bastos
- Institut Pasteur, Biology and genetics of the bacterial cell wall Unit, 25-28 rue du Docteur Roux, Paris 75724, France; CNRS, UMR 2001 "Microbiologie intégrative et moléculaire", Paris 75015, France.,Université de Paris, Sorbonne Paris Cité, 12 rue de l'Ecole de Médecine, 75006, Paris, France
| | - Richard Wheeler
- Institut Pasteur, Biology and genetics of the bacterial cell wall Unit, 25-28 rue du Docteur Roux, Paris 75724, France; CNRS, UMR 2001 "Microbiologie intégrative et moléculaire", Paris 75015, France.,Tumour Immunology and Immunotherapy, Institut Gustave Roussy, 114 rue Edouard-Vaillant, Villejuif 94800, France; INSERM UMR 1015, Villejuif 94800, France
| | - Ivo G Boneca
- Institut Pasteur, Biology and genetics of the bacterial cell wall Unit, 25-28 rue du Docteur Roux, Paris 75724, France; CNRS, UMR 2001 "Microbiologie intégrative et moléculaire", Paris 75015, France
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45
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Apostolos AJ, Ferraro NJ, Dalesandro BE, Pires MM. SaccuFlow: A High-Throughput Analysis Platform to Investigate Bacterial Cell Wall Interactions. ACS Infect Dis 2021; 7:2483-2491. [PMID: 34291914 DOI: 10.1021/acsinfecdis.1c00255] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Bacterial cell walls are formidable barriers that protect bacterial cells against external insults and oppose internal turgor pressure. While cell wall composition is variable across species, peptidoglycan is the principal component of all cell walls. Peptidoglycan is a mesh-like scaffold composed of cross-linked strands that can be heavily decorated with anchored proteins. The biosynthesis and remodeling of peptidoglycan must be tightly regulated by cells because disruption to this biomacromolecule is lethal. This essentiality is exploited by the human innate immune system in resisting colonization and by a number of clinically relevant antibiotics that target peptidoglycan biosynthesis. Evaluation of molecules or proteins that interact with peptidoglycan can be a complicated and, typically, qualitative effort. We have developed a novel assay platform (SaccuFlow) that preserves the native structure of bacterial peptidoglycan and is compatible with high-throughput flow cytometry analysis. We show that the assay is facile and versatile as demonstrated by its compatibility with sacculi from Gram-positive bacteria, Gram-negative bacteria, and mycobacteria. Finally, we highlight the utility of this assay to assess the activity of sortase A from Staphylococcus aureus against potential antivirulence agents.
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Affiliation(s)
- Alexis J. Apostolos
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States
| | - Noel J. Ferraro
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States
| | - Brianna E. Dalesandro
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States
| | - Marcos M. Pires
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States
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46
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Duxbury Z, Wu CH, Ding P. A Comparative Overview of the Intracellular Guardians of Plants and Animals: NLRs in Innate Immunity and Beyond. ANNUAL REVIEW OF PLANT BIOLOGY 2021; 72:155-184. [PMID: 33689400 DOI: 10.1146/annurev-arplant-080620-104948] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Nucleotide-binding domain leucine-rich repeat receptors (NLRs) play important roles in the innate immune systems of both plants and animals. Recent breakthroughs in NLR biochemistry and biophysics have revolutionized our understanding of how NLR proteins function in plant immunity. In this review, we summarize the latest findings in plant NLR biology and draw direct comparisons to NLRs of animals. We discuss different mechanisms by which NLRs recognize their ligands in plants and animals. The discovery of plant NLR resistosomes that assemble in a comparable way to animal inflammasomes reinforces the striking similarities between the formation of plant and animal NLR complexes. Furthermore, we discuss the mechanisms by which plant NLRs mediate immune responses and draw comparisons to similar mechanisms identified in animals. Finally, we summarize the current knowledge of the complex genetic architecture formed by NLRs in plants and animals and the roles of NLRs beyond pathogen detection.
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Affiliation(s)
- Zane Duxbury
- Jealott's Hill International Research Centre, Syngenta, Bracknell RG42 6EY, United Kingdom;
| | - Chih-Hang Wu
- Institute of Plant and Microbial Biology, Academia Sinica, Taipei 11529, Taiwan;
| | - Pingtao Ding
- The Sainsbury Laboratory, University of East Anglia, Norwich NR4 7UH, United Kingdom
- Current affiliation: Institute of Biology Leiden, Leiden University, Leiden 2333 BE, The Netherlands;
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47
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Guzelj S, Nabergoj S, Gobec M, Pajk S, Klančič V, Slütter B, Frkanec R, Štimac A, Šket P, Plavec J, Mlinarič-Raščan I, Jakopin Ž. Structural Fine-Tuning of Desmuramylpeptide NOD2 Agonists Defines Their In Vivo Adjuvant Activity. J Med Chem 2021; 64:7809-7838. [PMID: 34043358 PMCID: PMC8279416 DOI: 10.1021/acs.jmedchem.1c00644] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
![]()
We
report on the design, synthesis, and biological evaluation of
a series of nucleotide-binding oligomerization-domain-containing protein
2 (NOD2) desmuramylpeptide agonists with improved in vitro and in vivo adjuvant properties. We identified
two promising compounds: 68, a potent nanomolar in vitro NOD2 agonist, and the more lipophilic 75, which shows superior adjuvant activity in vivo. Both compounds had immunostimulatory effects on peripheral blood
mononuclear cells at the protein and transcriptional levels, and augmented
dendritic-cell-mediated activation of T cells, while 75 additionally enhanced the cytotoxic activity of peripheral blood
mononuclear cells against malignant cells. The C18 lipophilic
tail of 75 is identified as a pivotal structural element
that confers in vivo adjuvant activity in conjunction
with a liposomal delivery system. Accordingly, liposome-encapsulated 75 showed promising adjuvant activity in mice, surpassing
that of muramyl dipeptide, while achieving a more balanced Th1/Th2
immune response, thus highlighting its potential as a vaccine adjuvant.
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Affiliation(s)
- Samo Guzelj
- Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, Slovenia
| | - Sanja Nabergoj
- Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, Slovenia
| | - Martina Gobec
- Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, Slovenia
| | - Stane Pajk
- Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, Slovenia
| | - Veronika Klančič
- Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, Slovenia
| | - Bram Slütter
- Div. BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands
| | - Ruža Frkanec
- Centre for Research and Knowledge Transfer in Biotechnology, University of Zagreb, 10000 Zagreb, Croatia
| | - Adela Štimac
- Centre for Research and Knowledge Transfer in Biotechnology, University of Zagreb, 10000 Zagreb, Croatia
| | - Primož Šket
- Slovenian NMR Centre, National Institute of Chemistry, SI-1000 Ljubljana, Slovenia
| | - Janez Plavec
- Slovenian NMR Centre, National Institute of Chemistry, SI-1000 Ljubljana, Slovenia
| | | | - Žiga Jakopin
- Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, Slovenia
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48
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Bersch K, DeMeester KE, Zagani R, Chen S, Wodzanowski KA, Liu S, Mashayekh S, Reinecker HC, Grimes CL. Bacterial Peptidoglycan Fragments Differentially Regulate Innate Immune Signaling. ACS CENTRAL SCIENCE 2021; 7:688-696. [PMID: 34056099 PMCID: PMC8155477 DOI: 10.1021/acscentsci.1c00200] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Indexed: 05/07/2023]
Abstract
The human innate immune system responds to both pathogen and commensal bacteria at the molecular level using bacterial peptidoglycan (PG) recognition elements. Traditionally, synthetic and commercially accessible PG monosaccharide units known as muramyl dipeptide (MDP) and N-glycolyl MDP (ng-MDP) have been used to probe the mechanism of innate immune activation of pattern recognition receptors, such as NOD-like receptors. However, bacterial PG is a dynamic and complex structure, with various chemical modifications and trimming mechanisms that result in the production of disaccharide-containing elements. These molecules pose as attractive targets for immunostimulatory screening; however, studies are limited because of their synthetic accessibility. Inspired by disaccharide-containing compounds produced from the gut microbe Lactobacillus acidophilus, a robust and scalable chemical synthesis of PG-based disaccharide ligands was implemented. Together with a monosaccharide PG library, compounds were screened for their ability to stimulate proinflammatory genes in bone-marrow-derived macrophages. The data reveal distinct gene induction patterns for monosaccharide and disaccharide PG units, suggesting that PG innate immune signaling is more complex than a one activator-one pathway program, as biologically relevant fragments induce transcriptional programs to different degrees. These disaccharide molecules will serve as critical immunostimulatory tools to more precisely define specialized innate immune regulatory mechanisms that distinguish between commensal and pathogenic bacteria residing in the microbiome.
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Affiliation(s)
- Klare
L. Bersch
- Department
of Chemistry and Biochemistry, University
of Delaware, Newark, Delaware 19716, United States
| | - Kristen E. DeMeester
- Department
of Chemistry and Biochemistry, University
of Delaware, Newark, Delaware 19716, United States
| | - Rachid Zagani
- Department
of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory
Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, United States
| | - Shuyuan Chen
- Department
of Medicine, Division of Digestive and Liver Diseases, and Department
of Immunology, University of Texas Southwestern
Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas 75390, United
States
| | - Kimberly A. Wodzanowski
- Department
of Chemistry and Biochemistry, University
of Delaware, Newark, Delaware 19716, United States
| | - Shuzhen Liu
- Department
of Medicine, Division of Digestive and Liver Diseases, and Department
of Immunology, University of Texas Southwestern
Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas 75390, United
States
| | - Siavash Mashayekh
- Department
of Chemistry and Biochemistry, University
of Delaware, Newark, Delaware 19716, United States
| | - Hans-Christian Reinecker
- Department
of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory
Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, United States
- Department
of Medicine, Division of Digestive and Liver Diseases, and Department
of Immunology, University of Texas Southwestern
Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas 75390, United
States
| | - Catherine L. Grimes
- Department
of Chemistry and Biochemistry, University
of Delaware, Newark, Delaware 19716, United States
- Department
of Biological Sciences, University of Delaware, Newark, Delaware 19716, United States
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49
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Fani Maleki A, Cisbani G, Laflamme N, Prefontaine P, Plante MM, Baillargeon J, Rangachari M, Gosselin J, Rivest S. Selective Immunomodulatory and Neuroprotective Effects of a NOD2 Receptor Agonist on Mouse Models of Multiple Sclerosis. Neurotherapeutics 2021; 18:889-904. [PMID: 33479802 PMCID: PMC8423880 DOI: 10.1007/s13311-020-00998-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2020] [Indexed: 12/13/2022] Open
Abstract
The significance of monocytes has been demonstrated in multiple sclerosis (MS). One of the therapeutic challenges is developing medications that induce mild immunomodulation that is solely targeting specific monocyte subsets without affecting microglia. Muramyl dipeptide (MDP) activates the NOD2 receptor, and systemic MDP administrations convert Ly6Chigh into Ly6Clow monocytes. Here, we report selective immunomodulatory and therapeutic effects of MDP on cuprizone and experimental autoimmune encephalomyelitis (EAE) mouse models of MS. MDP treatment exerted various therapeutic effects in EAE, including delaying EAE onset and reducing infiltration of leukocytes into the CNS before EAE onset. Of great interest is the robust beneficial effect of the MDP treatment in mice already developing the disease several days after EAE onset. Finally, we found that the NOD2 receptor plays a critical role in MDP-mediated EAE resistance. Our results demonstrate that MDP is beneficial in both early and progressive phases of EAE. Based on these results, and upon comprehensive basic and clinical research, we anticipate developing NOD2 agonist-based medications for MS in the future.
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MESH Headings
- Acetylmuramyl-Alanyl-Isoglutamine/pharmacology
- Acetylmuramyl-Alanyl-Isoglutamine/therapeutic use
- Adjuvants, Immunologic/pharmacology
- Adjuvants, Immunologic/therapeutic use
- Animals
- Disease Models, Animal
- Encephalomyelitis, Autoimmune, Experimental/chemically induced
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/prevention & control
- Freund's Adjuvant/toxicity
- Immunomodulating Agents/pharmacology
- Immunomodulating Agents/therapeutic use
- Male
- Mice
- Mice, Inbred C57BL
- Monocytes/drug effects
- Monocytes/immunology
- Multiple Sclerosis/chemically induced
- Multiple Sclerosis/immunology
- Multiple Sclerosis/prevention & control
- Myelin-Oligodendrocyte Glycoprotein/toxicity
- Neuroprotective Agents/pharmacology
- Neuroprotective Agents/therapeutic use
- Nod2 Signaling Adaptor Protein/agonists
- Peptide Fragments/toxicity
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Affiliation(s)
- Adham Fani Maleki
- Neuroscience Laboratory, CHU of Quebec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Boul., Quebec City, QC, G1V 4G2, Canada
| | - Giulia Cisbani
- Neuroscience Laboratory, CHU of Quebec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Boul., Quebec City, QC, G1V 4G2, Canada
| | - Nataly Laflamme
- Neuroscience Laboratory, CHU of Quebec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Boul., Quebec City, QC, G1V 4G2, Canada
| | - Paul Prefontaine
- Neuroscience Laboratory, CHU of Quebec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Boul., Quebec City, QC, G1V 4G2, Canada
| | - Marie-Michele Plante
- Neuroscience Laboratory, CHU of Quebec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Boul., Quebec City, QC, G1V 4G2, Canada
| | - Joanie Baillargeon
- Neuroscience Laboratory, CHU of Quebec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Boul., Quebec City, QC, G1V 4G2, Canada
| | - Manu Rangachari
- Neuroscience Laboratory, CHU of Quebec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Boul., Quebec City, QC, G1V 4G2, Canada
| | - Jean Gosselin
- Laboratory of Innate Immunity, CHU of Quebec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Boul., Quebec City, QC, G1V 4G2, Canada
| | - Serge Rivest
- Neuroscience Laboratory, CHU of Quebec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Boul., Quebec City, QC, G1V 4G2, Canada.
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Kim CS, Brown AM, Grove TZ, Etzkorn FA. Designed leucine-rich repeat proteins bind two muramyl dipeptide ligands. Protein Sci 2021; 30:804-817. [PMID: 33512005 DOI: 10.1002/pro.4031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 01/22/2021] [Accepted: 01/22/2021] [Indexed: 12/15/2022]
Abstract
Designed protein receptors hold diagnostic and therapeutic promise. We now report the design of five consensus leucine-rich repeat proteins (CLRR4-8) based on the LRR domain of nucleotide-binding oligomerization domain (NOD)-like receptors involved in the innate immune system. The CLRRs bind muramyl dipeptide (MDP), a bacterial cell wall component, with micromolar affinity. The overall Kd app values ranged from 1.0 to 57 μM as measured by fluorescence quenching experiments. Biphasic fluorescence quenching curves were observed in all CLRRs, with higher affinity Kd1 values ranging from 0.04 to 4.5 μM, and lower affinity Kd2 values ranging from 3.1 to 227 μM. These biphasic binding curves, along with the docking studies of MDP binding to CLRR4, suggest that at least two MDPs bind to each protein. Previously, only single MDP binding was reported. This high-capacity binding of MDP promises small, soluble, stable CLRR scaffolds as candidates for the future design of pathogen biosensors.
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Affiliation(s)
- Christina S Kim
- Department of Chemistry, Virginia Tech, Blacksburg, Virginia, USA
| | - Anne M Brown
- University Libraries, Virginia Tech, Blacksburg, Virginia, USA
| | - Tijana Z Grove
- Department of Chemistry, Virginia Tech, Blacksburg, Virginia, USA
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