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Rodrigues CS, Gaifem J, Pereira MS, Alves MF, Silva M, Padrão N, Cavadas B, Moreira-Barbosa C, Alves I, Marcos-Pinto R, Torres J, Lavelle A, Colombel JF, Sokol H, Pinho SS. Alterations in mucosa branched N-glycans lead to dysbiosis and downregulation of ILC3: a key driver of intestinal inflammation. Gut Microbes 2025; 17:2461210. [PMID: 39918275 PMCID: PMC11810091 DOI: 10.1080/19490976.2025.2461210] [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: 08/29/2024] [Revised: 11/29/2024] [Accepted: 01/13/2025] [Indexed: 02/12/2025] Open
Abstract
The perturbation of the symbiotic relationship between microbes and intestinal immune system contributes to gut inflammation and Inflammatory Bowel Disease (IBD) development. The host mucosa glycans (glycocalyx) creates a major biological interface between gut microorganisms and host immunity that remains ill-defined. Glycans are essential players in IBD immunopathogenesis, even years before disease onset. However, how changes in mucosa glycosylation shape microbiome and how this impact gut immune response and inflammation remains to be clarified. Here, we revealed that alterations in the expression of complex branched N-glycans at gut mucosa surface, modeled in glycoengineered mice, resulted in dysbiosis, with a deficiency in Firmicutes bacteria. Concomitantly, this mucosa N-glycan switch was associated with a downregulation of type 3 innate lymphoid cells (ILC3)-mediated immune response, leading to the transition of ILC3 toward an ILC1 proinflammatory phenotype and increased TNFα production. In addition, we demonstrated that the mucosa glycosylation remodeling through prophylactic supplementation with glycans at steady state was able to restore microbial-derived short-chain fatty acids and microbial sensing (by NOD2 expression) alongside the rescue of the expression of ILC3 module, suppressing intestinal inflammation and controlling disease onset. In a complementary approach, we further showed that IBD patients, often displaying dysbiosis, exhibited a tendency of decreased MGAT5 expression at epithelial cells that was accompanied by reduced ILC3 expression in gut mucosa. Altogether, these results unlock the effects of alterations in mucosa glycome composition in the regulation of the bidirectional crosstalk between microbiota and gut immune response, revealing host branched N-glycans/microbiota/ILC3 axis as an essential pathway in gut homeostasis and in preventing health to intestinal inflammation transition.
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Affiliation(s)
- Cláudia S. Rodrigues
- Institute for Research and Innovation in Health (i3S), Immunology, Cancer & Glycomedicine Group, University of Porto, Porto, Portugal
- School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal
| | - Joana Gaifem
- Institute for Research and Innovation in Health (i3S), Immunology, Cancer & Glycomedicine Group, University of Porto, Porto, Portugal
| | - Márcia S. Pereira
- Institute for Research and Innovation in Health (i3S), Immunology, Cancer & Glycomedicine Group, University of Porto, Porto, Portugal
- School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal
| | - Maria Francisca Alves
- Institute for Research and Innovation in Health (i3S), Immunology, Cancer & Glycomedicine Group, University of Porto, Porto, Portugal
- School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal
- Faculty of Sciences, University of Porto, Porto, Portugal
| | - Mariana Silva
- Institute for Research and Innovation in Health (i3S), Immunology, Cancer & Glycomedicine Group, University of Porto, Porto, Portugal
- School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal
| | - Nuno Padrão
- Institute for Research and Innovation in Health (i3S), Immunology, Cancer & Glycomedicine Group, University of Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
| | - Bruno Cavadas
- Institute for Research and Innovation in Health (i3S), Immunology, Cancer & Glycomedicine Group, University of Porto, Porto, Portugal
| | | | - Inês Alves
- Institute for Research and Innovation in Health (i3S), Immunology, Cancer & Glycomedicine Group, University of Porto, Porto, Portugal
| | - Ricardo Marcos-Pinto
- School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal
- Department of Gastroenterology, Centro Hospitalar do Porto, Porto, Portugal
- Centro de Investigação em Tecnologias e Serviços de Saúde, University of Porto, Porto, Portugal
| | - Joana Torres
- Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
- Faculty of Medicine, University of Lisbon, Lisbon, Portugal
- Division of Gastroenterology, Hospital da Luz, Lisbon, Portugal
| | - Aonghus Lavelle
- Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint-Antoine Hospital, Gastroenterology Department, Sorbonne Université, INSERM, Paris, France
| | - Jean-Frederic Colombel
- Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Harry Sokol
- Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint-Antoine Hospital, Gastroenterology Department, Sorbonne Université, INSERM, Paris, France
- INRAE, AgroParisTech, Micalis Institute, Université Paris-Saclay, Jouy-en-Josas, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, Paris, France
| | - Salomé S. Pinho
- Institute for Research and Innovation in Health (i3S), Immunology, Cancer & Glycomedicine Group, University of Porto, Porto, Portugal
- School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
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Chen S, Putnik R, Li X, Diwaker A, Vasconcelos M, Liu S, Gondi S, Zhou J, Guo L, Xu L, Temme S, Bersch K, Hyland S, Yin J, Burstein E, Bahnson BJ, Gildersleeve JC, Grimes CL, Reinecker HC. PGLYRP1-mediated intracellular peptidoglycan detection promotes intestinal mucosal protection. Nat Commun 2025; 16:1864. [PMID: 39984444 PMCID: PMC11845746 DOI: 10.1038/s41467-025-57126-9] [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: 10/02/2024] [Accepted: 02/10/2025] [Indexed: 02/23/2025] Open
Abstract
Peptidoglycan recognition proteins (PGLYRPs) are implicated in the control of the intestinal microbiota; however, molecular requirements for peptidoglycan (PGN) binding and receptor signaling mechanisms remain poorly understood. Here we show that PGLYRP1 is a receptor for the disaccharide motif of lysine N-acetylglucosamine N-acetylmuramic tripeptide (GMTriP-K). PGLYRP1 is required for innate immune activation by GMTriP-K but not muramyl dipeptide (MDP). In macrophages, intracellular PGLYRP1 complexes with NOD2 and GEF-H1, both of which are required for GMTriP-K-regulated gene expression. PGLYRP1 localizes to the endoplasmic reticulum and interacts at the Golgi with NOD2 upon GMTriP-K stimulation. PGLYRP1 and dependent gene expression signatures are induced in both mouse intestinal inflammation and human ulcerative colitis. Importantly, PGLYRP1 activation by GMTriP-K can result in the protection of mice from TNBS-induced colitis. Mammalian PGLYRPs can function as intracellular pattern recognition receptors for the control of host defense responses in the intestine.
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Affiliation(s)
- Shuyuan Chen
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Rachel Putnik
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Xi Li
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Alka Diwaker
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Marina Vasconcelos
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Shuzhen Liu
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Sudershan Gondi
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Junhui Zhou
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Lei Guo
- Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Lin Xu
- Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Sebastian Temme
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Klare Bersch
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Stephen Hyland
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Jianyi Yin
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ezra Burstein
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Brian J Bahnson
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Jeffrey C Gildersleeve
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | | | - Hans-Christian Reinecker
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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3
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Liang Y, Adamson C, Feng S, Qiao Y. Exploring the Impact of Amidation Status in Meso-Diaminopimelic-Acid-Containing Disaccharide Peptidoglycan Fragments on Host Innate Immune Activation. ACS Chem Biol 2025; 20:69-76. [PMID: 39749870 DOI: 10.1021/acschembio.4c00700] [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: 01/04/2025]
Abstract
Bacterial peptidoglycan, the essential cell surface polymer that protects bacterial integrity, also serves as the molecular pattern recognized by the host's innate immune system. Although the minimal motifs of bacterial peptidoglycan fragments (PGNs) that activate mammalian NOD1 and NOD2 sensors are well-known and often represented by small canonical ligands, the immunostimulatory effects of natural PGNs, which are structurally more complex and potentially can simultaneously activate both the NOD1 and NOD2 signaling pathways in hosts, have not been comprehensively investigated. In particular, many bacteria incorporate additional structural modifications in peptidoglycans to evade host immune surveillance, resulting in diverse structural variations among natural PGNs that may influence their biological effects in hosts. The focus of this study is on the amidation status of γ-d-glutamic acid and meso-diaminopimelic acid (mDAP) at the second and third positions of stem peptides in peptidoglycan, which represent key structural features that vary across different bacterial species. With four synthetic mDAP-containing disaccharide PGNs of different amidation states, we systematically investigated their structure-activity relationship in stimulating host innate immune responses in vitro. Our findings revealed that the amidation of disaccharide PGNs has distinct effects on NOD1 and NOD2 induction, along with their differential immunostimulatory activities in macrophage cells. Additionally, we found that, like the canonical NOD2 ligand, natural PGNs confer immune tolerance to LPS, and amidation states do not affect this outcome. Overall, our work highlights the potential immunological implications of these differentially amidated mDAP-type disaccharide PGNs in host-microbe crosstalk.
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Affiliation(s)
- Yaquan Liang
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 637371, Singapore
| | - Christopher Adamson
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 637371, Singapore
| | - Shiliu Feng
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 637371, Singapore
| | - Yuan Qiao
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 637371, Singapore
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Dixon CL, Martin NR, Niphakis MJ, Cravatt BF, Fairn GD. Attenuating ABHD17 isoforms augments the S-acylation and function of NOD2 and a subset of Crohn's disease-associated NOD2 variants. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2023.12.20.572362. [PMID: 38187608 PMCID: PMC10769251 DOI: 10.1101/2023.12.20.572362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
BACKGROUND AND AIMS NOD2 is an intracellular innate immune receptor that detects bacterial peptidoglycan fragments. Although nominally soluble, some NOD2 is associated with the plasma membrane and endosomal compartments for microbial surveillance. This membrane targeting is achieved through post-translational S-acylation of NOD2 by the protein acyltransferase ZDHHC5. Membrane attachment is necessary to initiate a signaling cascade in response to cytosolic peptidoglycan fragments. Ultimately, this signaling results in the production of antimicrobial peptides and pro-inflammatory cytokines. In most cases, S-acylation is a reversible post-translational modification with removal of the fatty acyl chain catalyzed by one of several acyl protein thioesterases. Deacylation of NOD2 by such an enzyme will displace it from the plasma membrane and endosomes, thus preventing signaling. METHODS To identify the enzymes responsible for NOD2 deacylation, we used engineered cell lines with RNA interference and small-molecule inhibitors. These approaches were combined with confocal microscopy, acyl-resin-assisted capture, immunoblotting, and cytokine multiplex assays. RESULTS We identified α/β-hydrolase domain-containing protein 17 isoforms (ABHD17A, ABHD17B, and ABHD17C) as the acyl protein thioesterases responsible for NOD2 deacylation. Inhibiting ABHD17 increased the plasma membrane localization of wild-type NOD2 and a subset of poorly acylated Crohn's disease-associated variants. This enhanced NOD2 activity, increasing NF-κB activation and pro-inflammatory cytokine production in epithelial cells. CONCLUSIONS These findings demonstrate that ABHD17 isoforms are negative regulators of NOD2. The results also suggest that targeting ABHD17 isoforms could restore functionality to specific Crohn's disease-associated NOD2 variants, offering a potential therapeutic strategy.
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Affiliation(s)
- Charneal L. Dixon
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada
| | - Noah R. Martin
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | | | | | - Gregory D. Fairn
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada
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5
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Shen J, Lou L, Du X, Zhou B, Xu Y, Mei F, Wu L, Li J, Waisman A, Ruan J, Wang X. YOD1 sustains NOD2-mediated protective signaling in colitis by stabilizing RIPK2. EMBO Rep 2024; 25:4827-4845. [PMID: 39333628 PMCID: PMC11549337 DOI: 10.1038/s44319-024-00276-6] [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: 03/08/2024] [Revised: 09/03/2024] [Accepted: 09/18/2024] [Indexed: 09/29/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a disorder causing chronic inflammation in the gastrointestinal tract, and its pathophysiological mechanisms are still under investigation. Here, we find that mice deficient of YOD1, a deubiquitinating enzyme, are highly susceptible to dextran sulfate sodium (DSS)-induced colitis. The bone marrow transplantation experiment reveals that YOD1 derived from hematopoietic cells inhibits DSS colitis. Moreover, YOD1 exerts its protective role by promoting nucleotide-binding oligomerization domain 2 (NOD2)-mediated physiological inflammation in macrophages. Mechanistically, YOD1 inhibits the proteasomal degradation of receptor-interacting serine/threonine kinase 2 (RIPK2) by reducing its K48 polyubiquitination, thereby increasing RIPK2 abundance to enhance NOD2 signaling. Consistently, the protective function of muramyldipeptide, a NOD2 ligand, in experimental colitis is abolished in mice deficient of YOD1. Importantly, YOD1 is upregulated in colon-infiltrating macrophages in patients with colitis. Collectively, this study identifies YOD1 as a novel regulator of colitis.
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Affiliation(s)
- Jiangyun Shen
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
| | - Liyan Lou
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
| | - Xue Du
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
| | - Bincheng Zhou
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
| | - Yanqi Xu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
| | - Fuqi Mei
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
| | - Liangrong Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
- Department of Pharmacy, Yiwu Central Hospital, 322099, Yiwu, China
| | - Jianmin Li
- Department of Pathology, The First Affiliated Hospital, Wenzhou Medical University, 325000, Wenzhou, China
| | - Ari Waisman
- Institute for Molecular Medicine, Johannes Gutenberg University Mainz, 55131, Mainz, Germany
| | - Jing Ruan
- Department of Pathology, The First Affiliated Hospital, Wenzhou Medical University, 325000, Wenzhou, China.
| | - Xu Wang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China.
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Chen S, Putnik R, Li X, Diwaker A, Vasconcelos M, Liu S, Zhou J, Guo L, Xu L, Temme S, Bersch K, Hyland S, Yin J, Burstein E, Gildersleeve JC, Grimes CL, Reinecker HC. PGLYRP-1 mediated intracellular peptidoglycan detection promotes mucosal protection. RESEARCH SQUARE 2024:rs.3.rs-5118704. [PMID: 39483916 PMCID: PMC11527351 DOI: 10.21203/rs.3.rs-5118704/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Peptidoglycan recognition proteins (PGRPs or PGLYRPs) are implicated in the control of the intestinal microbiota; however, molecular requirements for peptidoglycan (PGN) binding and receptor signaling mechanisms remain poorly understood. We identified PGLYRP-1 as a receptor for the disaccharide motif of lysine N-acetylglucosamine N-acetylmuramic tripeptide (GMTriP-K) with a newly constructed PGN microarray. Surprisingly, PGLYRP-1 was required for innate immune activation of macrophages by GMTriP-K but not N-acetylglucosamine N-acetylmuramic dipeptide (GMDiP) or muramyl dipeptide (MDP). In macrophages, intracellular PGLYRP-1 complexed with NOD2 and GEF-H1, both of which were required for GMTriP-K-regulated gene expression. PGLYRP-1 localized to the endoplasmic reticulum and interacted at the Golgi with NOD2 upon GMTriP-K stimulation. PGLYRP-1 upregulation and its dependent gene expression signatures were induced in both mouse intestinal inflammation and human ulcerative colitis. Importantly, PGLYRP-1 activation by GMTriP-K resulted in innate immune activation and protection of mice from colitis. Our results show that PGLYRPs can function as intracellular PGN pattern recognition receptors for the control of host defense responses in the intestine.
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Affiliation(s)
- Shuyuan Chen
- Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas 75390, United States
| | - Rachel Putnik
- Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States National Cancer Institute
| | - Xi Li
- Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas 75390, United States
| | - Alka Diwaker
- Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas 75390, United States
| | - Marina Vasconcelos
- Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States National Cancer Institute
| | - Shuzhen Liu
- Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas 75390, United States
| | - Junhui Zhou
- Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States National Cancer Institute
| | - Lei Guo
- Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, United States
| | - Lin Xu
- Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, United States
| | - Sebastian Temme
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, United States
| | - Klare Bersch
- Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States National Cancer Institute
| | - Stephen Hyland
- Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States National Cancer Institute
| | - Jianyi Yin
- Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas 75390, United States
| | - Ezra Burstein
- Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas 75390, United States
| | - Jeffrey C. Gildersleeve
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, United States
| | - Catherine Leimkuhler Grimes
- Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States National Cancer Institute
| | - Hans-Christian Reinecker
- Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas 75390, United States
- Department of Immunology, Center for the Genetics of Host Defense, and Simmons Cancer Center University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas 75390, United States
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7
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Chang C, Louie A, Zhou Y, Gupta R, Liang F, Xanthou G, Ereso J, Koletic C, Yang JC, Sedighian F, Lagishetty V, Arias-Jayo N, Altuwayjiri A, Tohidi R, Navab M, Reddy ST, Sioutas C, Hsiai T, Araujo JA, Jacobs JP. Ambient Particulate Matter Induces In Vitro Toxicity to Intestinal Epithelial Cells without Exacerbating Acute Colitis Induced by Dextran Sodium Sulfate or 2,4,6-Trinitrobenzenesulfonic Acid. Int J Mol Sci 2024; 25:7184. [PMID: 39000289 PMCID: PMC11241079 DOI: 10.3390/ijms25137184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/14/2024] [Accepted: 06/20/2024] [Indexed: 07/16/2024] Open
Abstract
Inflammatory bowel disease (IBD) is an immunologically complex disorder involving genetic, microbial, and environmental risk factors. Its global burden has continued to rise since industrialization, with epidemiological studies suggesting that ambient particulate matter (PM) in air pollution could be a contributing factor. Prior animal studies have shown that oral PM10 exposure promotes intestinal inflammation in a genetic IBD model and that PM2.5 inhalation exposure can increase intestinal levels of pro-inflammatory cytokines. PM10 and PM2.5 include ultrafine particles (UFP), which have an aerodynamic diameter of <0.10 μm and biophysical and biochemical properties that promote toxicity. UFP inhalation, however, has not been previously studied in the context of murine models of IBD. Here, we demonstrated that ambient PM is toxic to cultured Caco-2 intestinal epithelial cells and examined whether UFP inhalation affected acute colitis induced by dextran sodium sulfate and 2,4,6-trinitrobenzenesulfonic acid. C57BL/6J mice were exposed to filtered air (FA) or various types of ambient PM reaerosolized in the ultrafine size range at ~300 μg/m3, 6 h/day, 3-5 days/week, starting 7-10 days before disease induction. No differences in weight change, clinical disease activity, or histology were observed between the PM and FA-exposed groups. In conclusion, UFP inhalation exposure did not exacerbate intestinal inflammation in acute, chemically-induced colitis models.
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Affiliation(s)
- Candace Chang
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (C.C.); (Y.Z.); (F.L.); (G.X.); (J.E.); (C.K.); (J.C.Y.); (F.S.); (V.L.); (N.A.-J.)
- Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.L.); (R.G.); (M.N.); (S.T.R.); (T.H.)
- Department of Environmental Health Sciences, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA
- Molecular Toxicology Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Allen Louie
- Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.L.); (R.G.); (M.N.); (S.T.R.); (T.H.)
- Department of Environmental Health Sciences, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA
- Molecular Toxicology Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Yi Zhou
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (C.C.); (Y.Z.); (F.L.); (G.X.); (J.E.); (C.K.); (J.C.Y.); (F.S.); (V.L.); (N.A.-J.)
- West China Medical Center, Sichuan University, Chengdu 610017, China
| | - Rajat Gupta
- Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.L.); (R.G.); (M.N.); (S.T.R.); (T.H.)
- Department of Environmental Health Sciences, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA
- Molecular Toxicology Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Fengting Liang
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (C.C.); (Y.Z.); (F.L.); (G.X.); (J.E.); (C.K.); (J.C.Y.); (F.S.); (V.L.); (N.A.-J.)
| | - Georgina Xanthou
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (C.C.); (Y.Z.); (F.L.); (G.X.); (J.E.); (C.K.); (J.C.Y.); (F.S.); (V.L.); (N.A.-J.)
| | - Jason Ereso
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (C.C.); (Y.Z.); (F.L.); (G.X.); (J.E.); (C.K.); (J.C.Y.); (F.S.); (V.L.); (N.A.-J.)
| | - Carolina Koletic
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (C.C.); (Y.Z.); (F.L.); (G.X.); (J.E.); (C.K.); (J.C.Y.); (F.S.); (V.L.); (N.A.-J.)
| | - Julianne Ching Yang
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (C.C.); (Y.Z.); (F.L.); (G.X.); (J.E.); (C.K.); (J.C.Y.); (F.S.); (V.L.); (N.A.-J.)
| | - Farzaneh Sedighian
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (C.C.); (Y.Z.); (F.L.); (G.X.); (J.E.); (C.K.); (J.C.Y.); (F.S.); (V.L.); (N.A.-J.)
| | - Venu Lagishetty
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (C.C.); (Y.Z.); (F.L.); (G.X.); (J.E.); (C.K.); (J.C.Y.); (F.S.); (V.L.); (N.A.-J.)
| | - Nerea Arias-Jayo
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (C.C.); (Y.Z.); (F.L.); (G.X.); (J.E.); (C.K.); (J.C.Y.); (F.S.); (V.L.); (N.A.-J.)
| | - Abdulmalik Altuwayjiri
- USC Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA; (A.A.); (R.T.); (C.S.)
- Department of Civil and Environmental Engineering, College of Engineering, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Ramin Tohidi
- USC Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA; (A.A.); (R.T.); (C.S.)
- Air Quality Planning and Science Division, California Air Resources Board, 4001 Iowa Avenue, Riverside, CA 92507, USA
| | - Mohamad Navab
- Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.L.); (R.G.); (M.N.); (S.T.R.); (T.H.)
| | - Srinivasa Tadiparthi Reddy
- Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.L.); (R.G.); (M.N.); (S.T.R.); (T.H.)
- West China Medical Center, Sichuan University, Chengdu 610017, China
- Molecular & Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Constantinos Sioutas
- USC Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA; (A.A.); (R.T.); (C.S.)
| | - Tzung Hsiai
- Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.L.); (R.G.); (M.N.); (S.T.R.); (T.H.)
- Henry Samueli School of Engineering, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Jesus A. Araujo
- Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.L.); (R.G.); (M.N.); (S.T.R.); (T.H.)
- Department of Environmental Health Sciences, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA
- Molecular Toxicology Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Jonathan P. Jacobs
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (C.C.); (Y.Z.); (F.L.); (G.X.); (J.E.); (C.K.); (J.C.Y.); (F.S.); (V.L.); (N.A.-J.)
- Molecular Toxicology Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
- Goodman-Luskin Microbiome Center, University of California Los Angeles, Los Angeles, CA 90095, USA
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8
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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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9
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Hardtke-Wolenski M, Landwehr-Kenzel S. Tipping the balance in autoimmunity: are regulatory t cells the cause, the cure, or both? Mol Cell Pediatr 2024; 11:3. [PMID: 38507159 PMCID: PMC10954601 DOI: 10.1186/s40348-024-00176-8] [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: 10/22/2023] [Accepted: 03/07/2024] [Indexed: 03/22/2024] Open
Abstract
Regulatory T cells (Tregs) are a specialized subgroup of T-cell lymphocytes that is crucial for maintaining immune homeostasis and preventing excessive immune responses. Depending on their differentiation route, Tregs can be subdivided into thymically derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which originate from conventional T cells after extrathymic differentiation at peripheral sites. Although the regulatory attributes of tTregs and pTregs partially overlap, their modes of action, protein expression profiles, and functional stability exhibit specific characteristics unique to each subset. Over the last few years, our knowledge of Treg differentiation, maturation, plasticity, and correlations between their phenotypes and functions has increased. Genetic and functional studies in patients with numeric and functional Treg deficiencies have contributed to our mechanistic understanding of immune dysregulation and autoimmune pathologies. This review provides an overview of our current knowledge of Treg biology, discusses monogenetic Treg pathologies and explores the role of Tregs in various other autoimmune disorders. Additionally, we discuss novel approaches that explore Tregs as targets or agents of innovative treatment options.
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Affiliation(s)
- Matthias Hardtke-Wolenski
- Hannover Medical School, Department of Gastroenterology Hepatology, Infectious Diseases and Endocrinology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
- University Hospital Essen, Institute of Medical Microbiology, University Duisburg-Essen, Hufelandstraße 55, Essen, 45122, Germany
| | - Sybille Landwehr-Kenzel
- Hannover Medical School, Department of Pediatric Pneumology, Allergology and Neonatology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
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10
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Okai N, Masuta Y, Otsuka Y, Hara A, Masaki S, Kamata K, Minaga K, Honjo H, Kudo M, Watanabe T. Crosstalk between NOD2 and TLR2 suppresses the development of TLR2-mediated experimental colitis. J Clin Biochem Nutr 2024; 74:146-153. [PMID: 38510686 PMCID: PMC10948350 DOI: 10.3164/jcbn.23-87] [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: 09/25/2023] [Accepted: 12/12/2023] [Indexed: 03/22/2024] Open
Abstract
Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular sensor for muramyl dipeptide (MDP), a degradation product of bacterial cell wall peptidoglycan (PGN). PGN stimulates cell-surface Toll-like receptor 2 (TLR2) independently of NOD2, indicating the presence of crosstalk between extracellular TLR2 and intracellular NOD2 upon exposure to PGN. NOD2-deficient mice were sensitive, while TLR2-deficient mice were resistant to experimental colitis induced by intrarectal administration of PGN. Severe colitis in NOD2-deficient mice was accompanied by increased expression of nuclear factor-kappa B-dependent cytokines and decreased expression of autophagy-related 16-like 1 (ATG16L1). MDP activation of NOD2 enhanced autophagy mediated by TLR2 in human dendritic cells. mRNA expression of TLR2 tended to be higher in the colonic mucosa of patients with active ulcerative colitis compared to that of those in remission. Induction of remission was associated with increased mRNA expression of ATG16L1 in both ulcerative colitis and Crohn's disease patients. Conversely, mRNA expression of receptor-interacting serine/threonine-protein kinase 2 was higher in the inflammatory colonic mucosa of patients with active disease than in the non-inflamed mucosa of patients in remission, in both ulcerative colitis and Crohn's disease. These findings highlight the role of NOD2-TLR2 crosstalk in the immunopathogenesis of colitis.
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Affiliation(s)
- Natsuki Okai
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Yasuhiro Masuta
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Yasuo Otsuka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Akane Hara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Sho Masaki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Hajime Honjo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
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11
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Orsini Delgado ML, Gamelas Magalhaes J, Morra R, Cultrone A. Muropeptides and muropeptide transporters impact on host immune response. Gut Microbes 2024; 16:2418412. [PMID: 39439228 PMCID: PMC11509177 DOI: 10.1080/19490976.2024.2418412] [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: 07/15/2024] [Revised: 10/04/2024] [Accepted: 10/10/2024] [Indexed: 10/25/2024] Open
Abstract
In bacteria, the cell envelope is the key element surrounding and protecting the bacterial content from mechanical or osmotic damages. It allows the selective interchanges of solutes, ions, cellular debris, and drugs between the cellular compartments and the external environment, thanks to the presence of transmembrane proteins called transporters. The major component of the cell envelope is the peptidoglycan, consisting of long linear glycan strands cross-linked by short peptide stems. During cell growth or under stress conditions, peptidoglycan fragments, the muropeptides, are released by bacteria and recognized by the host Pattern Recognition Receptor, promoting the activation of their innate defense mechanisms. The review sums up the salient aspects of microbiota-host interaction with a focus on the NOD-dependent immune response to bacterial peptidoglycan and on the accountability of muropeptide transporters in the crosstalk with the host and in antibiotic resistance. Furthermore, it retraces the discoveries and applications of microorganisms-derived components such as vaccines or vaccine adjuvants.
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12
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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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13
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Chauvin C, Radulovic K, Boulard O, Delacre M, Waldschmitt N, Régnier P, Legris G, Bouchez C, Sleimi MY, Rosenstiel P, Darrasse-Jèze G, Chamaillard M, Poulin LF. Loss of NOD2 in macrophages improves colitis and tumorigenesis in a lysozyme-dependent manner. Front Immunol 2023; 14:1252979. [PMID: 37876927 PMCID: PMC10590911 DOI: 10.3389/fimmu.2023.1252979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/14/2023] [Indexed: 10/26/2023] Open
Abstract
Background Crohn's disease (CD) is a complex and poorly understood myeloid-mediated disorder. Genetic variants with loss of function in the NOD2 gene confer an increased susceptibility to ileal CD. While Nod2 in myeloid cells may confer protection against T-cell mediated ileopathy, it remains unclear whether it may promote resolution of the inflamed colon. In this study, we evaluated the function of Nod2 in myeloid cells in a model of acute colitis and colitis-associated colon cancer (CAC). Methods To ablate Nod2 specifically within the myeloid compartment, we generated LysMCre/+;Nod2fl/fl mice. The role of NOD2 was studied in a setting of Dextran Sodium Sulfate (DSS)-induced colitis and in azoxymethane (AOM)/DSS model. Clinical parameters were quantified by colonoscopy, histological, flow cytometry, and qRT-PCR analysis. Results Upon DSS colitis model, LysMCre/+;Nod2fl/fl mice lost less weight than control littermates and had less severe damage to the colonic epithelium. In the AOM/DSS model, endoscopic monitoring of tumor progression revealed a lowered number of adenomas within the colon of LysMCre/+;Nod2fl/fl mice, associated with less expression of Tgfb. Mechanistically, lysozyme M was required for the improved disease severity in mice with a defect of NOD2 in myeloid cells. Conclusion Our results indicate that loss of Nod2 signaling in myeloid cells aids in the tissue repair of the inflamed large intestine through lysozyme secretion by myeloid cells. These results may pave the way to design new therapeutics to limit the inflammatory and tumorigenic functions of NOD2.
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Affiliation(s)
- Camille Chauvin
- Univ. Lille, Institut National de la Santé Et de la Recherche Médicale (Inserm), Centre de Recherche Hospitalier Universitaire (CHU) Lille, Institut Pasteur de Lille, U1019, Lille, France
- Institut national de la santé et de la recherche médicale (INSERM) U1138, Centre de Recherche des Cordeliers, Paris, France
| | - Katarina Radulovic
- Unité de Recherche Clinique, Centre Hospitalier de Valenciennes, Valenciennes, France
| | | | - Myriam Delacre
- Univ. Lille, Institut National de la Santé Et de la Recherche Médicale (Inserm), Centre de Recherche Hospitalier Universitaire (CHU) Lille, Institut Pasteur de Lille, U1019, Lille, France
| | - Nadine Waldschmitt
- Chair of Nutrition and Immunology, School of Life Sciences, Technische Universität München, Freising-Weihenstephan, Germany
| | - Paul Régnier
- Immunology-Immunopathology-Immunotherapy (i3) Laboratory, Institut national de la santé et de la recherche médicale (INSERM) UMR-S 959, Sorbonne Université, Paris, France
- Biotherapy Unit (CIC-BTi), Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | | | | | | | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany
| | - Guillaume Darrasse-Jèze
- Immunology-Immunopathology-Immunotherapy (i3) Laboratory, Institut national de la santé et de la recherche médicale (INSERM) UMR-S 959, Sorbonne Université, Paris, France
- Université de Paris, Paris Descartes, Faculté de Médecine, Paris, France
- Université Paris Cité, Faculté de Médecine, Paris, France
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14
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Masuta Y, Otsuka Y, Minaga K, Honjo H, Kudo M, Watanabe T. Regulation of type I IFN responses by deubiquitinating enzyme A in inflammatory bowel diseases. J Clin Biochem Nutr 2023; 73:103-107. [PMID: 37700847 PMCID: PMC10493212 DOI: 10.3164/jcbn.23-24] [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: 04/13/2023] [Accepted: 06/21/2023] [Indexed: 09/14/2023] Open
Abstract
The development of Inflammatory bowel disease (IBD) is driven by excessive production of pro-inflammatory cytokines including TNF-α, IL-12, and IL-23. This notion is supported by the remarkable clinical success of biologics targeting these cytokines. Recognition of cell wall components derived from intestinal bacteria by Toll-like receptors (TLRs) induces the production of these pro-inflammatory cytokines by macrophages and dendritic cells in human IBD and experimental colitis model. Although sensing of bacterial nucleic acids by endosomal TLRs, specifically TLR3, TLR7, and TLR9 leads to robust production of type I IFNs, it remains debatable whether TLR-mediated type I IFN responses are pathogenic or protective in IBD patients. Additionally, recent studies identified deubiquitinating enzyme A (DUBA) as a novel negative regulator of TLR-mediated type I IFN responses. In light of these observations and their potential applications, in this review, we summarize recent findings on the roles of type I IFN responses and DUBA-mediated negative regulation of these responses in human IBD and experimental colitis model.
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Affiliation(s)
- Yasuhiro Masuta
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Yasuo Otsuka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Hajime Honjo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
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15
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Gao J, Wang L, Jiang J, Xu Q, Zeng N, Lu B, Yuan P, Sun K, Zhou H, He X. A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice. Nat Commun 2023; 14:3338. [PMID: 37286542 PMCID: PMC10247697 DOI: 10.1038/s41467-023-38950-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 05/23/2023] [Indexed: 06/09/2023] Open
Abstract
Secreted proteins are one of the direct molecular mechanisms by which microbiota influence the host, thus constituting a promising field for drug discovery. Here, through bioinformatics-guided screening of the secretome of clinically established probiotics from Lactobacillus, we identify an uncharacterized secreted protein (named LPH here) that is shared by most of these probiotic strains (8/10) and demonstrate that it protects female mice from colitis in multiple models. Functional studies show that LPH is a bi-functional peptidoglycan hydrolase with both N-Acetyl-β-D-muramidase and DL-endopeptidase activities that can generate muramyl dipeptide (MDP), a NOD2 ligand. Different active site mutants of LPH in combination with Nod2 knockout female mice confirm that LPH exerts anti-colitis effects through MDP-NOD2 signaling. Furthermore, we validate that LPH can also exert protective effects on inflammation-associated colorectal cancer in female mice. Our study reports a probiotic enzyme that enhances NOD2 signaling in vivo in female mice and describes a molecular mechanism that may contribute to the effects of traditional Lactobacillus probiotics.
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Affiliation(s)
- Jie Gao
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China
| | - Lei Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China
| | - Jing Jiang
- Department Gerontology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, 610072, Chengdu, Sichuan, China
| | - Qian Xu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China
| | - Nianyi Zeng
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China
| | - Bingyun Lu
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, 518101, Shenzhen, Guangdong, China
| | - Peibo Yuan
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China
| | - Kai Sun
- Department of General Surgery, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China.
| | - Hongwei Zhou
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China.
- State Key Laboratory of Organ Failure Research, Southern Medical University, 510655, Guangzhou, Guangdong, China.
| | - Xiaolong He
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China.
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16
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Masyutina AM, Maximchik PV, Chkadua GZ, Pashenkov MV. Inhibition of specific signaling pathways rather than epigenetic silencing of effector genes is the leading mechanism of innate tolerance. Front Immunol 2023; 14:1006002. [PMID: 36776861 PMCID: PMC9909295 DOI: 10.3389/fimmu.2023.1006002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 01/09/2023] [Indexed: 01/27/2023] Open
Abstract
Introduction Macrophages activated through a pattern-recognition receptor (PRR) enter a transient state of tolerance characterized by diminished responsiveness to restimulation of the same receptor. Signaling-based and epigenetic mechanisms are invoked to explain this innate tolerance. However, these two groups of mechanisms should result in different outcomes. The epigenetic scenario (silencing of effector genes) predicts that activation of a PRR should broadly cross-tolerize to agonists of unrelated PRRs, whereas in the signaling-based scenario (inhibition of signaling pathways downstream of specific PRRs), cross-tolerization should occur only between agonists utilizing the same PRR and/or signaling pathway. Also, the so-called non-tolerizeable genes have been described, which acquire distinct epigenetic marks and increased responsiveness to rechallenge with the same agonist. The existence of such genes is well explained by epigenetic mechanisms but difficult to explain solely by signaling mechanisms. Methods To evaluate contribution of signaling and epigenetic mechanisms to innate tolerance, we tolerized human macrophages with agonists of TLR4 or NOD1 receptors, which signal via distinct pathways, and assessed responses of tolerized cells to homologous restimulation and to cross-stimulation using different signaling, metabolic and transcriptomic read-outs. We developed a transcriptomics-based approach to distinguish responses to secondary stimulation from continuing responses to primary stimulation. Results We found that macrophages tolerized with a NOD1 agonist lack responses to homologous restimulation, whereas LPS-tolerized macrophages partially retain the ability to activate NF-κB pathway upon LPS rechallenge, which allows to sustain low-level expression of a subset of pro-inflammatory genes. Contributing to LPS tolerance is blockade of signaling pathways required for IFN-β production, resulting in 'pseudo-tolerization' of IFN-regulated genes. Many genes in NOD1- or TLR4-tolerized macrophages are upregulated as the result of primary stimulation (due to continuing transcription and/or high mRNA stability), but do not respond to homologous restimulation. Hyperresponsiveness of genes to homologous rechallenge is a rare and inconsistent phenomenon. However, most genes that have become unresponsive to homologous stimuli show unchanged or elevated responses to agonists of PRRs signaling via distinct pathways. Discussion Thus, inhibition of specific signaling pathways rather than epigenetic silencing is the dominant mechanism of innate tolerance.
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Affiliation(s)
- Anna M. Masyutina
- Laboratory of Clinical Immunology, National Research Center “Institute of Immunology” of the Federal Medical-Biological Agency of Russia, Moscow, Russia,Biological Faculty, Lomonosov Moscow State University, Moscow, Russia
| | - Polina V. Maximchik
- Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Georgy Z. Chkadua
- Laboratory of experimental diagnostics and biotherapy of tumors, N.N.Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Mikhail V. Pashenkov
- Laboratory of Clinical Immunology, National Research Center “Institute of Immunology” of the Federal Medical-Biological Agency of Russia, Moscow, Russia,*Correspondence: Mikhail V. Pashenkov,
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17
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You Y, Xiao Y, Lu Y, Du J, Cai H, Cai W, Yan W. Postbiotic muramyl dipeptide alleviates colitis via activating autophagy in intestinal epithelial cells. Front Pharmacol 2022; 13:1052644. [PMID: 36506547 PMCID: PMC9727138 DOI: 10.3389/fphar.2022.1052644] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 11/07/2022] [Indexed: 11/24/2022] Open
Abstract
The pathogenesis of IBD is complicated and still unclear. Nucleotide-binding oligomerization domain 2 (NOD2) plays a significant role in regulating gut inflammation under the activation of muramyl dipeptide (MDP), which is used as a postbiotic. The study aimed to investigate the effect of MDP on the intestinal barrier in colitis and the mechanism involved. In this study, C57BL/6 mice were challenged with dextran sodium sulfate (DSS) for establishing a colitis model with the pre-treatment of MDP in vivo. Intestinal permeability was reflected by detecting the serum concentration of 4 kDa Fluorescein Isothiocyanate-Dextran. The expression of inflammation, barrier-related proteins, and autophagy was tested by Western Blotting. Proliferation and apoptosis in intestinal epithelial cells were detected by immunohistochemistry. Caco-2 cells were exposed to lipopolysaccharide for imitating inflammation in vitro. The findings showed that administration of MDP ameliorated losses of body weight loss, gross injury, and histology score of the colon in the DSS-induced colitis mice. MDP significantly ameliorated the condition of gut permeability, and promoted intestinal barrier repair by increasing the expression of Zonula occludens-1 and E-cadherin. Meanwhile, MDP promoted proliferation and reduced apoptosis of intestinal epithelial cells. In the experiment group treated with MDP, LC3 was upregulated, and p62 was downregulated, respectively. These results suggested that MDP stimulation attenuates intestinal inflammation both in vivo and in vitro. Potentially, MDP reduced the intestinal barrier damage by regulating autophagy in intestinal epithelial cells. Future trials investigating the effects of MDP-based postbiotics on IBD may be promising.
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Affiliation(s)
- Yaying You
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Yongtao Xiao
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Ying Lu
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Jun Du
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Hui Cai
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Wei Cai
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China,*Correspondence: Weihui Yan, ; Wei Cai,
| | - Weihui Yan
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China,*Correspondence: Weihui Yan, ; Wei Cai,
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18
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Zhai F, Wang J, Yang W, Ye M, Jin X. The E3 Ligases in Cervical Cancer and Endometrial Cancer. Cancers (Basel) 2022; 14:5354. [PMID: 36358773 PMCID: PMC9658772 DOI: 10.3390/cancers14215354] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/25/2022] [Accepted: 10/27/2022] [Indexed: 07/28/2023] Open
Abstract
Endometrial (EC) and cervical (CC) cancers are the most prevalent malignancies of the female reproductive system. There is a global trend towards increasing incidence and mortality, with a decreasing age trend. E3 ligases label substrates with ubiquitin to regulate their activity and stability and are involved in various cellular functions. Studies have confirmed abnormal expression or mutations of E3 ligases in EC and CC, indicating their vital roles in the occurrence and progression of EC and CC. This paper provides an overview of the E3 ligases implicated in EC and CC and discusses their underlying mechanism. In addition, this review provides research advances in the target of ubiquitination processes in EC and CC.
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Affiliation(s)
- Fengguang Zhai
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China
| | - Jie Wang
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China
| | - Weili Yang
- Department of Gynecology, The Affiliated People’s Hospital of Ningbo University, Ningbo 315040, China
| | - Meng Ye
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China
| | - Xiaofeng Jin
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China
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19
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Omaru N, Watanabe T, Kamata K, Minaga K, Kudo M. Activation of NOD1 and NOD2 in the development of liver injury and cancer. Front Immunol 2022; 13:1004439. [PMID: 36268029 PMCID: PMC9577175 DOI: 10.3389/fimmu.2022.1004439] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/16/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatocytes and liver-resident antigen-presenting cells are exposed to microbe-associated molecular patterns (MAMPs) and microbial metabolites, which reach the liver from the gut via the portal vein. MAMPs induce innate immune responses via the activation of pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), nucleotide-binding oligomerization domain 1 (NOD1), and NOD2. Such proinflammatory cytokine responses mediated by PRRs likely contribute to the development of chronic liver diseases and hepatocellular carcinoma (HCC), as shown by the fact that activation of TLRs and subsequent production of IL-6 and TNF-α is required for the generation of chronic fibroinflammatory responses and hepatocarcinogenesis. Similar to TLRs, NOD1 and NOD2 recognize MAMPs derived from the intestinal bacteria. The association between the activation of NOD1/NOD2 and chronic liver diseases is poorly understood. Given that NOD1 and NOD2 can regulate proinflammatory cytokine responses mediated by TLRs both positively and negatively, it is likely that sensing of MAMPs by NOD1 and NOD2 affects the development of chronic liver diseases, including HCC. Indeed, recent studies have highlighted the importance of NOD1 and NOD2 activation in chronic liver disorders. Here, we summarize the roles of NOD1 and NOD2 in hepatocarcinogenesis and liver injury.
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20
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Okai N, Watanabe T, Minaga K, Kamata K, Honjo H, Kudo M. Alterations of autophagic and innate immune responses by the Crohn’s disease-associated ATG16L1 mutation. World J Gastroenterol 2022; 28:3063-3070. [PMID: 36051337 PMCID: PMC9331526 DOI: 10.3748/wjg.v28.i26.3063] [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: 01/10/2022] [Revised: 04/21/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
Crohn’s disease (CD) is driven by the loss of tolerance to intestinal microbiota and excessive production of pro-inflammatory cytokines. These pro-inflammatory cytokines are produced by macrophages and dendritic cells (DCs) upon sensing the intestinal microbiota by the pattern recognition receptors (PRRs). Impaired activation of PRR-mediated signaling pathways is associated with chronic gastrointestinal inflammation, as shown by the fact that loss-of-function mutations in the nucleotide-binding oligomerization domain 2 gene increase the risk of CD development. Autophagy is an intracellular degradation process, during which cytoplasmic nutrients and intracellular pathogens are digested. Given that impaired reaction to intestinal microbiota alters signaling pathways mediated by PRRs, it is likely that dysfunction of the autophagic machinery is involved in the development of CD. Indeed, the loss-of-function mutation T300A in the autophagy related 16 like 1 (ATG16L1) protein, a critical regulator of autophagy, increases susceptibility to CD. Recent studies have provided evidence that ATG16L1 is involved not only in autophagy, but also in PRR-mediated signaling pathways. ATG16L1 negatively regulates pro-inflammatory cytokine responses of macrophages and DCs after these cells sense the intestinal microbiota by PRRs. Here, we discuss the molecular mechanisms underlying the development of CD in the T300A ATG16L1 mutation by focusing on PRR-mediated signaling pathways.
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Affiliation(s)
- Natsuki Okai
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan
| | - Hajime Honjo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan
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21
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Nerb B, Dudziak D, Gessner A, Feuerer M, Ritter U. Have We Ignored Vector-Associated Microbiota While Characterizing the Function of Langerhans Cells in Experimental Cutaneous Leishmaniasis? FRONTIERS IN TROPICAL DISEASES 2022. [DOI: 10.3389/fitd.2022.874081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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22
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Abraham C, Abreu MT, Turner JR. Pattern Recognition Receptor Signaling and Cytokine Networks in Microbial Defenses and Regulation of Intestinal Barriers: Implications for Inflammatory Bowel Disease. Gastroenterology 2022; 162:1602-1616.e6. [PMID: 35149024 PMCID: PMC9112237 DOI: 10.1053/j.gastro.2021.12.288] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 11/30/2021] [Accepted: 12/10/2021] [Indexed: 12/23/2022]
Abstract
Inflammatory bowel disease is characterized by defects in epithelial function and dysregulated inflammatory signaling by lamina propria mononuclear cells including macrophages and dendritic cells in response to microbiota. In this review, we focus on the role of pattern recognition receptors in the inflammatory response as well as epithelial barrier regulation. We explore cytokine networks that increase inflammation, regulate paracellular permeability, cause epithelial damage, up-regulate epithelial proliferation, and trigger restitutive processes. We focus on studies using patient samples as well as speculate on pathways that can be targeted to more holistically treat patients with inflammatory bowel disease.
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Affiliation(s)
- Clara Abraham
- Department of Internal Medicine, Yale University, New Haven, Connecticut.
| | - Maria T. Abreu
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Miami Leonard Miller School of Medicine, Miami, FL
| | - Jerrold R. Turner
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
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23
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Masaki S, Watanabe T, Arai Y, Sekai I, Hara A, Kurimoto M, Otsuka Y, Masuta Y, Yoshikawa T, Takada R, Kamata K, Minaga K, Yamashita K, Kudo M. Expression levels of cellular inhibitor of apoptosis proteins and colitogenic cytokines are inversely correlated with the activation of interferon regulatory factor 4. Clin Exp Immunol 2022; 207:340-350. [PMID: 35553628 PMCID: PMC9113101 DOI: 10.1093/cei/uxac005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 01/04/2022] [Accepted: 01/11/2022] [Indexed: 01/19/2023] Open
Abstract
Cellular inhibitors of apoptosis proteins 1 (cIAP1) and 2 (cIAP2) are involved in signaling pathways mediated by Toll-like receptors (TLRs) and tumor necrosis factor (TNF)-α. Excessive activation of TLRs and TNF-α underlies the immunopathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). However, the roles played by cIAP1 and cIAP2 in the development of CD and UC remain poorly understood. In this study, we attempted to clarify the molecular link between cIAP1/cIAP2 and colonic inflammation. Human monocyte-derived dendritic cells (DCs) treated with siRNAs specific for cIAP1 or cIAP2 exhibited reduced pro-inflammatory cytokine responses upon stimulation with TLR ligands. Expression of cIAP1 and cIAP2 in human DCs was suppressed in the presence of interferon regulatory factor 4 (IRF4). This effect was associated with inhibition of cIAP1 and cIAP2 polyubiquitination. To verify these in vitro findings, we created mice overexpressing IRF4 in DCs and showed that these mice were resistant to trinitrobenzene sulfonic acid-induced colitis as compared with wild-type mice; these effects were accompanied by reduced expression levels of cIAP1 and cIAP2. Pro-inflammatory cytokine production by mesenteric lymph node cells upon stimulation with TLR ligands was reduced in mice with DC-specific IRF4 overexpression as compared with that in wild-type mice. Finally, in clinical samples of the colonic mucosa from patients with CD, there was a negative relationship between the percentage of IRF4+ DCs and percentages of cIAP1+ or cIAP2+ lamina propria mononuclear cells. These data suggest that the colitogenic roles of cIAP1 and cIAP2 are negatively regulated by IRF4.
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Affiliation(s)
- Sho Masaki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Tomohiro Watanabe
- Correspondence: Tomohiro Watanabe, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
| | - Yasuyuki Arai
- Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Ikue Sekai
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Akane Hara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Masayuki Kurimoto
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Yasuo Otsuka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Yasuhiro Masuta
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Tomoe Yoshikawa
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Ryutaro Takada
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Kouhei Yamashita
- Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
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24
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Ahmed I, Yusuf K, Roy BC, Stubbs J, Anant S, Attard TM, Sampath V, Umar S. Dietary Interventions Ameliorate Infectious Colitis by Restoring the Microbiome and Promoting Stem Cell Proliferation in Mice. Int J Mol Sci 2021; 23:339. [PMID: 35008767 PMCID: PMC8745185 DOI: 10.3390/ijms23010339] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/21/2021] [Accepted: 12/25/2021] [Indexed: 12/15/2022] Open
Abstract
Decreases in short-chain-fatty-acids (SCFAs) are linked to inflammatory bowel disease (IBD). Yet, the mechanisms through which SCFAs promote wound healing, orchestrated by intestinal stem cells, are poorly understood. We discovered that, in mice with Citrobacter rodentium (CR)-induced infectious colitis, treatment with Pectin and Tributyrin diets reduced the severity of colitis by restoring Firmicutes and Bacteroidetes and by increasing mucus production. RNA-seq in young adult mouse colon (YAMC) cells identified higher expression of Lgr4, Lgr6, DCLK1, Muc2, and SIGGIR after Butyrate treatment. Lineage tracing in CR-infected Lgr5-EGFP-IRES-CreERT2/ROSA26-LacZ (Lgr5-R) mice also revealed an expansion of LacZ-labeled Lgr5(+) stem cells in the colons of both Pectin and Tributyrin-treated mice compared to control. Interestingly, gut microbiota was required for Pectin but not Tributyrin-induced Lgr5(+) stem cell expansion. YAMC cells treated with sodium butyrate exhibited increased Lgr5 promoter reporter activity due to direct Butyrate binding with Lgr5 at -4.0 Kcal/mol, leading to thermal stabilization. Upon ChIP-seq, H3K4me3 increased near Lgr5 transcription start site that contained the consensus binding motif for a transcriptional activator of Lgr5 (SPIB). Thus, a multitude of effects on gut microbiome, differential gene expression, and/or expansion of Lgr5(+) stem cells seem to underlie amelioration of colitis following dietary intervention.
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Affiliation(s)
- Ishfaq Ahmed
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA; (I.A.); (K.Y.); (B.C.R.)
| | - Kafayat Yusuf
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA; (I.A.); (K.Y.); (B.C.R.)
| | - Badal C. Roy
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA; (I.A.); (K.Y.); (B.C.R.)
| | - Jason Stubbs
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA;
| | - Shrikant Anant
- Cancer Biology Department, University of Kansas Medical Center, Kansas City, KS 66160, USA;
| | - Thomas M. Attard
- Department of Pediatrics and Gastroenterology, Children’s Mercy Hospital, Kansas City, KS 66160, USA; (T.M.A.); (V.S.)
| | - Venkatesh Sampath
- Department of Pediatrics and Gastroenterology, Children’s Mercy Hospital, Kansas City, KS 66160, USA; (T.M.A.); (V.S.)
| | - Shahid Umar
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA; (I.A.); (K.Y.); (B.C.R.)
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25
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Eshleman EM, Alenghat T. Epithelial sensing of microbiota-derived signals. Genes Immun 2021; 22:237-246. [PMID: 33824498 PMCID: PMC8492766 DOI: 10.1038/s41435-021-00124-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/10/2021] [Accepted: 03/16/2021] [Indexed: 02/01/2023]
Abstract
The gastrointestinal tract harbors trillions of microbial species, collectively termed the microbiota, which establish a symbiotic relationship with the host. Decades of research have emphasized the necessity of microbial signals in the development, maturation, and function of host physiology. However, changes in the composition or containment of the microbiota have been linked to the development of several chronic inflammatory diseases, including inflammatory bowel diseases. Intestinal epithelial cells (IECs) are in constant contact with the microbiota and are critical for maintaining intestinal homeostasis. Signals from the microbiota are directly sensed by IECs and influence intestinal health by calibrating immune cell responses and fortifying intestinal barrier function. IECs detect commensal microbes through engagement of common pattern recognition receptors or by sensing the production of microbial-derived metabolites. Deficiencies in these microbial-detecting pathways in IECs leads to impaired epithelial barrier function and altered intestinal homeostasis. This Review aims to highlight the pathways by which IECs sense microbiota-derived signals and the necessity of these detection pathways in maintaining epithelial barrier integrity.
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Affiliation(s)
- Emily M Eshleman
- Division of Immunobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Theresa Alenghat
- Division of Immunobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
- Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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26
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Honjo H, Watanabe T, Kamata K, Minaga K, Kudo M. RIPK2 as a New Therapeutic Target in Inflammatory Bowel Diseases. Front Pharmacol 2021; 12:650403. [PMID: 33935757 PMCID: PMC8079979 DOI: 10.3389/fphar.2021.650403] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/26/2021] [Indexed: 12/28/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are becoming more frequent worldwide. A significant fraction of patients with IBD are refractory to various types of therapeutic biologics and small molecules. Therefore, identification of novel therapeutic targets in IBD is required. Receptor-interacting serine/threonine kinase 2 (RIPK2), also known as receptor-interacting protein 2 (RIP2), is a downstream signaling molecule for nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs). RIPK2 is expressed in antigen-presenting cells, such as dendritic cells and macrophages. Recognition of microbe-associated molecular patterns by NOD1, NOD2, and TLRs leads to the interaction between RIPK2 and these innate immune receptors, followed by the release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12/23p40 through the activation of nuclear factor kappa B and mitogen-activated protein kinases. Thus, activation of RIPK2 plays a critical role in host defense against microbial infections. Recent experimental and clinical studies have provided evidence that activation of RIPK2 is involved in the development of autoimmune diseases, especially IBDs. In addition, the colonic mucosa of patients with IBD exhibits enhanced expression of RIPK2 and associated signaling molecules. Furthermore, the blockage of RIPK2 activation ameliorates the development of experimental murine colitis. Thus, activation of RIPK2 underlies IBD immunopathogenesis. In this review, we attempt to clarify the roles played by RIPK2 in the development of IBD by focusing on its associated signaling pathways. We also discuss the possibility of using RIPK2 as a new therapeutic target in IBD.
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Affiliation(s)
- Hajime Honjo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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27
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De Salvo C, Buela KA, Creyns B, Corridoni D, Rana N, Wargo HL, Cominelli CL, Delaney PG, Rodriguez-Palacios A, Cominelli F, Vermeire S, Pizarro TT. NOD2 drives early IL-33-dependent expansion of group 2 innate lymphoid cells during Crohn's disease-like ileitis. J Clin Invest 2021; 131:140624. [PMID: 33444291 DOI: 10.1172/jci140624] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 01/07/2021] [Indexed: 12/30/2022] Open
Abstract
Innate lymphoid cells (ILCs) are enriched at barrier surfaces, including the gastrointestinal tract. While most studies have focused on the balance between pathogenic group 1 ILCs (ILC1s) and protective ILC3s in maintaining gut homeostasis and during chronic intestinal inflammation, such as Crohn's disease (CD), less is known regarding ILC2s. Using an established murine model of CD-like ileitis, i.e., the SAMP1/YitFc (SAMP) mouse strain, we showed that ILC2s, compared with ILC1s and ILC3s, were increased within draining mesenteric lymph nodes and ilea of SAMP versus AKR (parental control) mice early, during the onset of disease. Gut-derived ILC2s from CD patients versus healthy controls were also increased and expanded, similarly to ILC1s, in greater proportion compared with ILC3s. Importantly, we report that the intracellular bacteria-sensing protein, nucleotide-binding oligomerization domaining-containing protein 2, encoded by Nod2, the first and strongest susceptibility gene identified for CD, promoted ILC2 expansion, which was dramatically reduced in SAMP mice lacking NOD2 and in SAMP mice raised under germ-free conditions. Furthermore, these effects occurred through a mechanism involving the IL-33/ST2 ligand-receptor pair. Collectively, our results indicate a functional link between NOD2 and ILC2s, regulated by the IL-33/ST2 axis, that mechanistically may contribute to early events leading to CD pathogenesis.
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Affiliation(s)
- Carlo De Salvo
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Kristine-Ann Buela
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Brecht Creyns
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, and.,Department of Chronic Diseases, Metabolism and Aging, TARGID, University Hospitals, KU Leuven, Leuven, Belgium
| | - Daniele Corridoni
- Department of Medicine and.,Department of Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA
| | - Nitish Rana
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Hannah L Wargo
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Chiara L Cominelli
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Peter G Delaney
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Alexander Rodriguez-Palacios
- Department of Medicine and.,Department of Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA
| | - Fabio Cominelli
- Department of Medicine and.,Department of Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA
| | - Séverine Vermeire
- Department of Chronic Diseases, Metabolism and Aging, TARGID, University Hospitals, KU Leuven, Leuven, Belgium.,Department of Gastroenterology, University Hospitals, KU Leuven, Leuven, Belgium
| | - Theresa T Pizarro
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.,Department of Medicine and
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Root-Bernstein R. Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions. Int J Mol Sci 2021; 22:ijms22042108. [PMID: 33672738 PMCID: PMC7924650 DOI: 10.3390/ijms22042108] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/12/2021] [Accepted: 02/14/2021] [Indexed: 01/08/2023] Open
Abstract
Severe COVID-19 is characterized by a “cytokine storm”, the mechanism of which is not yet understood. I propose that cytokine storms result from synergistic interactions among Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) due to combined infections of SARS-CoV-2 with other microbes, mainly bacterial and fungal. This proposition is based on eight linked types of evidence and their logical connections. (1) Severe cases of COVID-19 differ from healthy controls and mild COVID-19 patients in exhibiting increased TLR4, TLR7, TLR9 and NLRP3 activity. (2) SARS-CoV-2 and related coronaviruses activate TLR3, TLR7, RIG1 and NLRP3. (3) SARS-CoV-2 cannot, therefore, account for the innate receptor activation pattern (IRAP) found in severe COVID-19 patients. (4) Severe COVID-19 also differs from its mild form in being characterized by bacterial and fungal infections. (5) Respiratory bacterial and fungal infections activate TLR2, TLR4, TLR9 and NLRP3. (6) A combination of SARS-CoV-2 with bacterial/fungal coinfections accounts for the IRAP found in severe COVID-19 and why it differs from mild cases. (7) Notably, TLR7 (viral) and TLR4 (bacterial/fungal) synergize, TLR9 and TLR4 (both bacterial/fungal) synergize and TLR2 and TLR4 (both bacterial/fungal) synergize with NLRP3 (viral and bacterial). (8) Thus, a SARS-CoV-2-bacterium/fungus coinfection produces synergistic innate activation, resulting in the hyperinflammation characteristic of a cytokine storm. Unique clinical, experimental and therapeutic predictions (such as why melatonin is effective in treating COVID-19) are discussed, and broader implications are outlined for understanding why other syndromes such as acute lung injury, acute respiratory distress syndrome and sepsis display varied cytokine storm symptoms.
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Ghosh S, Whitley CS, Haribabu B, Jala VR. Regulation of Intestinal Barrier Function by Microbial Metabolites. Cell Mol Gastroenterol Hepatol 2021; 11:1463-1482. [PMID: 33610769 PMCID: PMC8025057 DOI: 10.1016/j.jcmgh.2021.02.007] [Citation(s) in RCA: 376] [Impact Index Per Article: 94.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 12/11/2022]
Abstract
The human gastrointestinal tract (GI) harbors a diverse population of microbial life that continually shapes host pathophysiological responses. Despite readily available abundant metagenomic data, the functional dynamics of gut microbiota remain to be explored in various health and disease conditions. Microbiota generate a variety of metabolites from dietary products that influence host health and pathophysiological functions. Since gut microbial metabolites are produced in close proximity to gut epithelium, presumably they have significant impact on gut barrier function and immune responses. The goal of this review is to discuss recent advances on gut microbial metabolites in the regulation of intestinal barrier function. While the mechanisms of action of these metabolites are only beginning to emerge, they mainly point to a small group of shared pathways that control gut barrier functions. Amidst expanding technology and broadening knowledge, exploitation of beneficial microbiota and their metabolites to restore pathophysiological balance will likely prove to be an extremely useful remedial tool.
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Affiliation(s)
- Sweta Ghosh
- Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Caleb Samuel Whitley
- Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Bodduluri Haribabu
- Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Venkatakrishna Rao Jala
- Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky.
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30
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Kienes I, Weidl T, Mirza N, Chamaillard M, Kufer TA. Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation. Int J Mol Sci 2021; 22:1301. [PMID: 33525590 PMCID: PMC7865845 DOI: 10.3390/ijms22031301] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.
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Affiliation(s)
- Ioannis Kienes
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
| | - Tanja Weidl
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
| | - Nora Mirza
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
| | | | - Thomas A. Kufer
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
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31
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Zangara MT, Johnston I, Johnson EE, McDonald C. Mediators of Metabolism: An Unconventional Role for NOD1 and NOD2. Int J Mol Sci 2021; 22:ijms22031156. [PMID: 33503814 PMCID: PMC7866072 DOI: 10.3390/ijms22031156] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/16/2021] [Accepted: 01/19/2021] [Indexed: 02/07/2023] Open
Abstract
In addition to their classical roles as bacterial sensors, NOD1 and NOD2 have been implicated as mediators of metabolic disease. Increased expression of NOD1 and/or NOD2 has been reported in a range of human metabolic diseases, including obesity, diabetes, non-alcoholic fatty liver disease, and metabolic syndrome. Although NOD1 and NOD2 share intracellular signaling pathway components, they are differentially upregulated on a cellular level and have opposing impacts on metabolic disease development in mouse models. These NOD-like receptors may directly mediate signaling downstream of cell stressors, such as endoplasmic reticulum stress and calcium influx, or in response to metabolic signals, such as fatty acids and glucose. Other studies suggest that stimulation of NOD1 or NOD2 by their bacterial ligands can result in inflammation, altered insulin responses, increased reactive oxygen signaling, and mitochondrial dysfunction. The activating stimuli for NOD1 and NOD2 in the context of metabolic disease are controversial and may be a combination of both metabolic and circulating bacterial ligands. In this review, we will summarize the current knowledge of how NOD1 and NOD2 may mediate metabolism in health and disease, as well as highlight areas of future investigation.
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Affiliation(s)
- Megan T. Zangara
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.Z.); (I.J.); (E.E.J.)
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Isabel Johnston
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.Z.); (I.J.); (E.E.J.)
| | - Erin E. Johnson
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.Z.); (I.J.); (E.E.J.)
- Department of Biology, John Carroll University, University Heights, OH 44118, USA
| | - Christine McDonald
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.Z.); (I.J.); (E.E.J.)
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Correspondence: ; Tel.: +1-216-445-7058
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The Impact of the NOD2/CARD15 Variant (3020insC) and PSMA6 Polymorphism (-8C>G) on the Development and Outcome of Multiple Myeloma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:7629456. [PMID: 32596371 PMCID: PMC7298267 DOI: 10.1155/2020/7629456] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 05/25/2020] [Indexed: 12/14/2022]
Abstract
Introduction Multiple myeloma (MM) is a hematological malignancy characterized by genetic variety. The 3020insC variant of the NOD2/CARD15 gene results in the upregulation of proinflammatory cytokines. Chronic inflammation and abnormal function of the proteasome system may lead to MM development. The polymorphism (-8C>G) in the PSMA6 gene affects proteasome activity. The aim of our study was to analyze the possible relationship of NOD/CARD15 and PSMA6 genes with the risk of development and outcome of MM, as well as the sensitivity to bortezomib (proteasome inhibitor) in cell cultures derived from MM patients. Objects and Methods. Genomic DNA from 100 newly diagnosed MM patients and 100 healthy blood donors was analyzed by methods such as PCR-RFLP (for PSMA6 genotyping) and automated DNA sequencing (for NOD2/CARD15 genotyping). In a subgroup of 50 MM patients, nucleated bone marrow cells were treated with bortezomib in vitro. Results Patients with PSMA6 CG+GG genotypes had higher chances for progressive disease (OR = 5.0, 95% CI 1.07-23.16, p = 0.05), shorter overall survival taking into account the type of treatment (p = 0.039), and increased risk of death due to MM at the level of tendency (OR = 4.74, 95% CI 1.02-21.97, p = 0.06). The presence of NOD2/CARD15 3020insC decreased the risk of renal dysfunction in MM (OR = 0.23, 95% CI 0.07-0.74, p = 0.009). The analyzed changes in NOD2/CARD15 and PSMA6 genes did not impact the MM risk. In an in vitro study, bortezomib increased the number of apoptotic cells at 8 nM and 12 nM between wild-type and 3030insC variants of NOD2/CARD15 (p = 0.018 and p = 0.03, respectively). Conclusion The presented results suggest a possible impact of PSMA6 CG+GG genotypes on the MM outcome and the association of the NOD2/CARD15 variant with bortezomib in vitro sensitivity.
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Mousavi S, Bereswill S, Heimesaat MM. Novel Clinical Campylobacter jejuni Infection Models Based on Sensitization of Mice to Lipooligosaccharide, a Major Bacterial Factor Triggering Innate Immune Responses in Human Campylobacteriosis. Microorganisms 2020; 8:E482. [PMID: 32231139 PMCID: PMC7232424 DOI: 10.3390/microorganisms8040482] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/25/2020] [Accepted: 03/26/2020] [Indexed: 12/12/2022] Open
Abstract
: Human Campylobacter jejuni infections inducing campylobacteriosis including post-infectious sequelae such as Guillain-Barré syndrome and reactive arthritis are rising worldwide and progress into a global burden of high socioeconomic impact. Intestinal immunopathology underlying campylobacteriosis is a classical response of the innate immune system characterized by the accumulation of neutrophils and macrophages which cause tissue destruction, barrier defects and malabsorption leading to bloody diarrhea. Clinical studies revealed that enteritis and post-infectious morbidities of human C. jejuni infections are strongly dependent on the structure of pathogenic lipooligosaccharides (LOS) triggering the innate immune system via Toll-like-receptor (TLR)-4 signaling. Compared to humans, mice display an approximately 10,000 times weaker TLR-4 response and a pronounced colonization resistance (CR) against C. jejuni maintained by the murine gut microbiota. In consequence, investigations of campylobacteriosis have been hampered by the lack of experimental animal models. We here summarize recent progress made in the development of murine C. jejuni infection models that are based on the abolishment of CR by modulating the murine gut microbiota and by sensitization of mice to LOS. These advances support the major role of LOS driven innate immunity in pathogenesis of campylobacteriosis including post-infectious autoimmune diseases and promote the preclinical evaluation of novel pharmaceutical strategies for prophylaxis and treatment.
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34
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Zhang L, Zhang B, Wei M, Xu Z, Kong W, Deng K, Xu X, Zhang L, Ζhao X, Yan L. TRIM22 inhibits endometrial cancer progression through the NOD2/NF‑κB signaling pathway and confers a favorable prognosis. Int J Oncol 2020; 56:1225-1239. [PMID: 32319602 PMCID: PMC7115357 DOI: 10.3892/ijo.2020.5004] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 02/20/2020] [Indexed: 12/15/2022] Open
Abstract
Endometrial cancer (EnC) is a malignant gynecological tumor commonly observed in developed countries, specifically among post‑menopausal women. Although numerous patients with EnC receive promising prognoses, those with advanced or metastatic disease often have a poor prognosis and an impaired quality of life. Tripartite motif‑containing 22 (TRIM22) has been confirmed to play many crucial roles in different biological processes, from inflammatory to tumorigenesis. However, the multifaceted roles of TRIM22 in EnC remain uncharacterized. Herein, comparing normal endometrial tissues with tumor tissues obtained from patients, it was concluded that TRIM22 expression was decreased in tumor tissues. However, the overexpression of TRIM22 served to inhibit the migratory, invasive, proliferative and cell cycle activity of EnC cells. Moreover, the knockdown of TRIM22 increased the migratory, invasive, and proliferative activity of the EnC cells. Furthermore, it was found that TRIM22 effectively suppressed EnC progression through the nucleotide binding oligomerization domain containing 2 (NOD2)/nuclear factor (NF)‑κB pathway. The data also demonstrated that TRIM22 functions as an inhibitor of EnC tumor xenograft growth in vivo. Overall, the findings of the present study define a novel regulatory role for TRIM22 in EnC progression. Moreover, TRIM22 may serve as an important prognostic predictor for EnC.
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Affiliation(s)
- Liping Zhang
- School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Bingqian Zhang
- School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Muyun Wei
- Department of Obstetrics and Gynecology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Zhen Xu
- School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Weiya Kong
- School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Ke Deng
- School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xinxin Xu
- Center for Reproductive Medicine, Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Lin Zhang
- Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province, Shandong University, Jinan, Shandong 250001, P.R. China
| | - Xingbo Ζhao
- Department of Obstetrics and Gynecology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Lei Yan
- School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
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35
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Umiker B, Lee HH, Cope J, Ajami NJ, Laine JP, Fregeau C, Ferguson H, Alves SE, Sciammetta N, Kleinschek M, Salmon M. The NLRP3 inflammasome mediates DSS-induced intestinal inflammation in Nod2 knockout mice. Innate Immun 2020; 25:132-143. [PMID: 30774010 PMCID: PMC6830860 DOI: 10.1177/1753425919826367] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Crohn’s disease (CD) is a chronic disorder of the gastrointestinal tract
characterized by inflammation and intestinal epithelial injury. Loss of function
mutations in the intracellular bacterial sensor NOD2 are major risk factors for
the development of CD. In the absence of robust bacterial recognition by NOD2 an
inflammatory cascade is initiated through alternative PRRs leading to CD. In the
present study, MCC950, a specific small molecule inhibitor of NLR pyrin
domain-containing protein 3 (NLRP3), abrogated dextran sodium sulfate
(DSS)-induced intestinal inflammation in Nod2−/−
mice. NLRP3 inflammasome formation was observed at a higher rate in
NOD2-deficient small intestinal lamina propria cells after insult by DSS. NLRP3
complex formation led to an increase in IL-1β secretion in both the small
intestine and colon of Nod2ko mice. This increase in IL-1β
secretion in the intestine was attenuated by MCC950 leading to decreased disease
severity in Nod2ko mice. Our work suggests that NLRP3
inflammasome activation may be a key driver of intestinal inflammation in the
absence of functional NOD2. NLRP3 pathway inhibition can prevent intestinal
inflammation in the absence of robust NOD2 signaling.
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Affiliation(s)
| | | | | | - Nadim J Ajami
- 2 Diversigen, Inc. Houston, TX, USA.,3 Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
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Heim VJ, Stafford CA, Nachbur U. NOD Signaling and Cell Death. Front Cell Dev Biol 2019; 7:208. [PMID: 31632962 PMCID: PMC6783575 DOI: 10.3389/fcell.2019.00208] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 09/11/2019] [Indexed: 01/18/2023] Open
Abstract
Innate immune signaling and programmed cell death are intimately linked, and many signaling pathways can regulate and induce both, transcription of inflammatory mediators or autonomous cell death. The best-characterized examples for these dual outcomes are members of the TNF superfamily, the inflammasome receptors, and the toll-like receptors. Signaling via the intracellular peptidoglycan receptors NOD1 and NOD2, however, does not appear to follow this trend, despite involving signaling proteins, or proteins with domains that are linked to programmed cell death, such as RIP kinases, inhibitors of apoptosis (IAP) proteins or the CARD domains on NOD1/2. To better understand the connections between NOD signaling and cell death induction, we here review the latest findings on the molecular regulation of signaling downstream of the NOD receptors and explore the links between this immune signaling pathway and the regulation of cell death.
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Affiliation(s)
- Valentin J Heim
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Che A Stafford
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Ueli Nachbur
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
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Takagawa T, Kitani A, Fuss I, Levine B, Brant SR, Peter I, Tajima M, Nakamura S, Strober W. An increase in LRRK2 suppresses autophagy and enhances Dectin-1-induced immunity in a mouse model of colitis. Sci Transl Med 2019; 10:10/444/eaan8162. [PMID: 29875204 DOI: 10.1126/scitranslmed.aan8162] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 05/23/2017] [Accepted: 12/19/2017] [Indexed: 12/17/2022]
Abstract
The LRRK2/MUC19 gene region constitutes a high-risk genetic locus for the occurrence of both inflammatory bowel diseases (IBDs) and Parkinson's disease. We show that dendritic cells (DCs) from patients with Crohn's disease (CD) and lymphoblastoid cell lines derived from patients without CD but bearing a high-risk allele (rs11564258) at this locus as heterozygotes exhibited increased LRRK2 expression in vitro. To investigate the immunological consequences of this increased LRRK2 expression, we conducted studies in transgenic mice overexpressing Lrrk2 and showed that these mice exhibited more severe colitis induced by dextran sodium sulfate (DSS) than did littermate control animals. This increase in colitis severity was associated with lamina propria DCs that showed increased Dectin-1-induced NF-κB activation and proinflammatory cytokine secretion. Colitis severity was driven by LRRK2 activation of NF-κB pathway components including the TAK1 complex and TRAF6. Next, we found that membrane-associated LRRK2 (in association with TAB2) caused inactivation of Beclin-1 and inhibition of autophagy. HCT116 colon epithelial cells lacking Beclin-1 exhibited increased LRRK2 expression compared to wild-type cells, suggesting that inhibition of autophagy potentially could augment LRRK2 proinflammatory signaling. We then showed that LRRK2 inhibitors decreased Dectin-1-induced TNF-α production by mouse DCs and ameliorated DSS-induced colitis, both in control and Lrrk2 transgenic animals. Finally, we demonstrated that LRRK2 inhibitors blocked TNF-α production by cultured DCs from patients with CD. Our findings suggest that normalization of LRRK2 activation could be a therapeutic approach for treating IBD, regardless of whether a LRRK2 risk allele is involved.
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Affiliation(s)
- Tetsuya Takagawa
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya 663-8501, Japan.,Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Atsushi Kitani
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ivan Fuss
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Beth Levine
- Departments of Internal Medicine and Microbiology, Center for Autophagy Research, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Steven R Brant
- Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins School of Medicine, and Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Inga Peter
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Masaki Tajima
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Shiro Nakamura
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya 663-8501, Japan
| | - Warren Strober
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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Lee J, Leichtle A, Zuckerman E, Pak K, Spriggs M, Wasserman SI, Kurabi A. NOD1/NOD2-mediated recognition of non-typeable Haemophilus influenzae activates innate immunity during otitis media. Innate Immun 2019; 25:503-512. [PMID: 31474163 PMCID: PMC6900663 DOI: 10.1177/1753425919872266] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Pathogen recognition following infection in mammals depends mainly on TLRs and
NLRs. Herein, we evaluate the role of NOD1 and NOD2 signaling in the
inflammatory responses of the middle ear (ME) mucosa and leukocytes recruitment
to infection site during otitis media (OM). OM is a common pediatric disease
with prevalent repercussions on hearing health. While many risk factors have
been implicated to OM proneness, immunity and the triggering of inflammation are
central to OM pathology. We observed that many genes encoding members of the NOD
leucine-rich repeat and their downstream adaptor/effector molecules were
strongly regulated during the course of OM. When compared to wild type C57BL/6
mice, NOD1- and NOD2-deficient mice were susceptible to prolonged OM infection
by non-typeable Haemophilus influenza. NOD1-deficient mice
appeared to have reduced macrophage enlistment with a delayed inflammatory
response by neutrophils and prolonged mucosal hyperplasia, whereas NOD2
knockouts exhibited an overall reduction in the number of leukocytes recruited
to the ME, leading to delayed bacterial clearance. Altogether, these data show
that the NODs play a role in the pathogenesis and recovery of OM and reinforce
the importance of innate immune signaling in the protective host response.
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Affiliation(s)
- Jasmine Lee
- Department of Surgery, University of California San Diego, USA
| | - Anke Leichtle
- Department of Surgery, University of California San Diego, USA.,Department of Otolaryngology, University of Lübeck, Germany
| | - Emily Zuckerman
- Department of Surgery, University of California San Diego, USA
| | - Kwang Pak
- Department of Surgery, University of California San Diego, USA.,San Diego Veterans Administration Healthcare System, La Jolla, CA, USA
| | - Meghan Spriggs
- Department of Surgery, University of California San Diego, USA
| | | | - Arwa Kurabi
- Department of Surgery, University of California San Diego, USA.,San Diego Veterans Administration Healthcare System, La Jolla, CA, USA
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Watanabe T, Minaga K, Kamata K, Sakurai T, Komeda Y, Nagai T, Kitani A, Tajima M, Fuss IJ, Kudo M, Strober W. RICK/RIP2 is a NOD2-independent nodal point of gut inflammation. Int Immunol 2019; 31:669-683. [PMID: 31132297 DOI: 10.1093/intimm/dxz045] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 05/25/2019] [Indexed: 12/19/2022] Open
Abstract
Previous studies have shown that inhibition of receptor-interacting serine/threonine kinase (RICK) (also known as RIP2) results in amelioration of experimental colitis. This role has largely been attributed to nucleotide-binding oligomerization domain 2 (NOD2) signaling since the latter is considered a major inducer of RICK activation. In this study, we explored the molecular mechanisms accounting for RICK-mediated inhibition of inflammatory bowel disease (IBD). In an initial series of studies focused on trinitrobenzene sulfonic acid (TNBS)-colitis and dextran sodium sulfate (DSS)-colitis we showed that down-regulation of intestinal RICK expression in NOD2-intact mice by intra-rectal administration of a plasmid expressing RICK-specific siRNA was accompanied by down-regulation of pro-inflammatory cytokine responses in the colon and protection of the mice from experimental colitis. Somewhat surprisingly, intra-rectal administration of RICK-siRNA also inhibited TNBS-colitis and DSS-colitis in NOD2-deficient and in NOD1/NOD2-double deficient mice. In complementary studies of humans with IBD we found that expression of RICK, cellular inhibitor of apoptosis protein 2 (cIAP2) and downstream signaling partners were markedly increased in inflamed tissue of IBD compared to controls without marked elevations of NOD1 or NOD2 expression. In addition, the increase in RICK expression correlated with disease activity and pro-inflammatory cytokine responses. These studies thus suggest that NOD1- or NOD2-independenent activation of RICK plays a major role in both murine experimental colitis and human IBD.
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Affiliation(s)
- Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Ohno-Higashi, Osaka-Sayama, Osaka, Japan.,Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Ohno-Higashi, Osaka-Sayama, Osaka, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Ohno-Higashi, Osaka-Sayama, Osaka, Japan
| | - Toshiharu Sakurai
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Ohno-Higashi, Osaka-Sayama, Osaka, Japan
| | - Yoriaki Komeda
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Ohno-Higashi, Osaka-Sayama, Osaka, Japan
| | - Tomoyuki Nagai
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Ohno-Higashi, Osaka-Sayama, Osaka, Japan
| | - Atsushi Kitani
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Masaki Tajima
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Ivan J Fuss
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Ohno-Higashi, Osaka-Sayama, Osaka, Japan
| | - Warren Strober
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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40
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Sun R, Hedl M, Abraham C. Twist1 and Twist2 Induce Human Macrophage Memory upon Chronic Innate Receptor Treatment by HDAC-Mediated Deacetylation of Cytokine Promoters. THE JOURNAL OF IMMUNOLOGY 2019; 202:3297-3308. [PMID: 31028123 DOI: 10.4049/jimmunol.1800757] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 04/01/2019] [Indexed: 12/19/2022]
Abstract
Intestinal tissues are continuously exposed to microbial products that stimulate pattern-recognition receptors (PRRs). Ongoing PRR stimulation can confer epigenetic changes in macrophages, which can then regulate subsequent immune outcomes and adaptation to the local environment. Mechanisms leading to these changes are incompletely understood. We found that short-term stimulation of the PRR NOD2 in primary human monocyte-derived macrophages resulted in increased H3 and H4 acetylation of cytokine promoters, consistent with the increased cytokine secretion observed. However, with prolonged NOD2 stimulation, both the acetylation and cytokine secretion were dramatically decreased. Chronic NOD2 stimulation upregulated the transcription factors Twist1 and Twist2, which bound to the promoters of the histone deacetylases HDAC1 and HDAC3 and induced HDAC1 and HDAC3 expression. HDAC1 and HDAC3 then mediated histone deacetylation at cytokine promoters and, in turn, cytokine downregulation under these conditions. Similar regulation was observed upon chronic stimulation of multiple PRRs. Consistent with the chronic microbial exposure in the intestinal environment, TWIST1, TWIST2, HDAC1, and HDAC3 were upregulated in human intestinal relative to peripheral macrophages. Importantly, complementing HDAC1 and HDAC3 in Twist1/Twist2-deficient monocyte-derived macrophages restored the reduced histone acetylation on cytokine promoters and the decreased cytokine secretion with chronic NOD2 stimulation. Taken together, we identify mechanisms wherein Twist1 and Twist2 promote chromatin modifications, resulting in macrophage instruction and adaptation to conditions in the intestinal microenvironment.
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Affiliation(s)
- Rui Sun
- Department of Internal Medicine, Yale University, New Haven, CT 06510
| | - Matija Hedl
- Department of Internal Medicine, Yale University, New Haven, CT 06510
| | - Clara Abraham
- Department of Internal Medicine, Yale University, New Haven, CT 06510
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41
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Zom GG, Willems MMJHP, Meeuwenoord NJ, Reintjens NRM, Tondini E, Khan S, Overkleeft HS, van der Marel GA, Codee JDC, Ossendorp F, Filippov DV. Dual Synthetic Peptide Conjugate Vaccine Simultaneously Triggers TLR2 and NOD2 and Activates Human Dendritic Cells. Bioconjug Chem 2019; 30:1150-1161. [PMID: 30865430 DOI: 10.1021/acs.bioconjchem.9b00087] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Simultaneous triggering of Toll-like receptors (TLRs) and NOD-like receptors (NLRs) has previously been shown to synergistically activate monocytes, dendritic cells, and macrophages. We applied these properties in a T-cell vaccine setting by conjugating the NOD2-ligand muramyl-dipeptide (MDP) and TLR2-ligand Pam3CSK4 to a synthetic peptide derived from a model antigen. Stimulation of human DCs with the MDP-peptide-Pam3CSK4 conjugate led to a strongly increased secretion of pro-inflammatory and Th1-type cytokines and chemokines. We further show that the conjugated ligands retain their ability to trigger their respective receptors, while even improving NOD2-triggering. Also, activation of murine DCs was enhanced by the dual triggering, ultimately leading to effective induction of vaccine-specific T cells expressing IFNγ, IL-2, and TNFα. Together, these data indicate that the dual MDP-SLP-Pam3CSK4 conjugate constitutes a chemically well-defined vaccine approach that holds promise for the use in the treatment of virus infections and cancer.
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Affiliation(s)
- Gijs G Zom
- Department of Immunohematology and Blood Transfusion , Leiden University Medical Center , P.O. Box 9600, 2300 RC Leiden , The Netherlands
| | - Marian M J H P Willems
- Leiden Institute of Chemistry , Leiden University , Einsteinweg 55 , 2333 CC Leiden , The Netherlands
| | - Nico J Meeuwenoord
- Leiden Institute of Chemistry , Leiden University , Einsteinweg 55 , 2333 CC Leiden , The Netherlands
| | - Niels R M Reintjens
- Leiden Institute of Chemistry , Leiden University , Einsteinweg 55 , 2333 CC Leiden , The Netherlands
| | - Elena Tondini
- Department of Immunohematology and Blood Transfusion , Leiden University Medical Center , P.O. Box 9600, 2300 RC Leiden , The Netherlands
| | - Selina Khan
- Department of Immunohematology and Blood Transfusion , Leiden University Medical Center , P.O. Box 9600, 2300 RC Leiden , The Netherlands
| | - Herman S Overkleeft
- Leiden Institute of Chemistry , Leiden University , Einsteinweg 55 , 2333 CC Leiden , The Netherlands
| | - Gijsbert A van der Marel
- Leiden Institute of Chemistry , Leiden University , Einsteinweg 55 , 2333 CC Leiden , The Netherlands
| | - Jeroen D C Codee
- Leiden Institute of Chemistry , Leiden University , Einsteinweg 55 , 2333 CC Leiden , The Netherlands
| | - Ferry Ossendorp
- Department of Immunohematology and Blood Transfusion , Leiden University Medical Center , P.O. Box 9600, 2300 RC Leiden , The Netherlands
| | - Dmitri V Filippov
- Leiden Institute of Chemistry , Leiden University , Einsteinweg 55 , 2333 CC Leiden , The Netherlands
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42
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NOD2 Expression in Intestinal Epithelial Cells Protects Toward the Development of Inflammation and Associated Carcinogenesis. Cell Mol Gastroenterol Hepatol 2018; 7:357-369. [PMID: 30704984 PMCID: PMC6357788 DOI: 10.1016/j.jcmgh.2018.10.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 10/11/2018] [Accepted: 10/15/2018] [Indexed: 12/12/2022]
Abstract
Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that senses bacterial peptidoglycan-conserved motifs in cytosol and stimulates host immune response including epithelial and immune cells. The association of NOD2 mutations with a number of inflammatory pathologies including Crohn's disease (CD), graft-versus-host diseases, or Blau syndrome, highlights its pivotal role in inflammatory response and the associated-carcinogenesis development. Since its identification in 2001 and its association with CD, the role of NOD2 in epithelial cells and immune cells has been investigated extensively but the precise mechanism by which NOD2 mutations lead to CD and the associated carcinogenesis development is largely unknown. In this review, we present and discuss recent developments about the role of NOD2 inside epithelial cells on the control of the inflammatory process and its linked carcinogenesis development.
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43
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McAlpine W, Wang KW, Choi JH, San Miguel M, McAlpine SG, Russell J, Ludwig S, Li X, Tang M, Zhan X, Choi M, Wang T, Bu CH, Murray AR, Moresco EMY, Turer EE, Beutler B. The class I myosin MYO1D binds to lipid and protects against colitis. Dis Model Mech 2018; 11:11/9/dmm035923. [PMID: 30279225 PMCID: PMC6176994 DOI: 10.1242/dmm.035923] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 08/02/2018] [Indexed: 12/12/2022] Open
Abstract
Myosin ID (MYO1D) is a member of the class I myosin family. We screened 48,649 third generation (G3) germline mutant mice derived from N-ethyl-N-nitrosourea-mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). We found and validated mutations in Myo1d as a cause of increased susceptibility to DSS-induced colitis. MYO1D is produced in the intestinal epithelium, and the colitis phenotype is dependent on the nonhematopoietic compartment of the mouse. Moreover, MYO1D appears to couple cytoskeletal elements to lipid in an ATP-dependent manner. These findings demonstrate that MYO1D is needed to maintain epithelial integrity and protect against DSS-induced colitis. Summary: Using random germline mutagenesis and screening of mice, we determined that loss of MYO1D function in nonhematopoietic tissues renders mice susceptible to colitis induced by dextran sodium sulfate challenge.
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Affiliation(s)
- William McAlpine
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Kuan-Wen Wang
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Jin Huk Choi
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Miguel San Miguel
- Department of Internal Medicine, Division of Gastroenterology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505 USA
| | - Sarah Grace McAlpine
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Jamie Russell
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Sara Ludwig
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Xiaohong Li
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Miao Tang
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Xiaoming Zhan
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Mihwa Choi
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Tao Wang
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA.,Quantitative Biomedical Research Center, Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Chun Hui Bu
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Anne R Murray
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Eva Marie Y Moresco
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
| | - Emre E Turer
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA.,Department of Internal Medicine, Division of Gastroenterology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505 USA
| | - Bruce Beutler
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA
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Askarian F, Wagner T, Johannessen M, Nizet V. Staphylococcus aureus modulation of innate immune responses through Toll-like (TLR), (NOD)-like (NLR) and C-type lectin (CLR) receptors. FEMS Microbiol Rev 2018; 42:656-671. [PMID: 29893825 PMCID: PMC6098222 DOI: 10.1093/femsre/fuy025] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 06/07/2018] [Indexed: 02/07/2023] Open
Abstract
Early recognition of pathogens by the innate immune system is crucial for bacterial clearance. Many pattern recognition receptors (PRRs) such as Toll-like (TLRs) and (NOD)-like (NLRs) receptors have been implicated in initial sensing of bacterial components. The intracellular signaling cascades triggered by these receptors result in transcriptional upregulation of inflammatory pathways. Although this step is crucial for bacterial elimination, it is also associated with the potential for substantial immunopathology, which underscores the need for tight control of inflammatory responses. The leading human bacterial pathogen Staphylococcus aureus expresses over 100 virulence factors that exert numerous effects upon host cells. In this manner, the pathogen seeks to avoid host recognition or perturb PRR-induced innate immune responses to allow optimal survival in the host. These immune system interactions may result in enhanced bacterial proliferation but also provoke systemic cytokine responses associated with sepsis. This review summarizes recent findings on the various mechanisms applied by S. aureus to modulate or interfere with inflammatory responses through PRRs. Detailed understanding of these complex interactions can provide new insights toward future immune-stimulatory therapeutics against infection or immunomodulatory therapeutics to suppress or correct dysregulated inflammation.
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Affiliation(s)
- Fatemeh Askarian
- Research Group of Host Microbe Interaction, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Tromsø, Norway
- Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego, La Jolla, CA 92093, USA
| | - Theresa Wagner
- Research Group of Host Microbe Interaction, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Tromsø, Norway
| | - Mona Johannessen
- Research Group of Host Microbe Interaction, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Tromsø, Norway
| | - Victor Nizet
- Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego, La Jolla, CA 92093, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA 92093, USA
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45
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Chiaranunt P, Tometich JT, Ji J, Hand TW. T Cell Proliferation and Colitis Are Initiated by Defined Intestinal Microbes. THE JOURNAL OF IMMUNOLOGY 2018; 201:243-250. [PMID: 29777027 DOI: 10.4049/jimmunol.1800236] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 04/23/2018] [Indexed: 12/22/2022]
Abstract
Inflammatory bowel disease has been associated with the dysregulation of T cells specific to Ags derived from the intestinal microbiota. How microbiota-specific T cells are regulated is not completely clear but is believed to be mediated by a combination of IgA, regulatory T cells, and type 3 innate lymphoid cells. To test the role of these regulatory components on microbiota-specific T cells, we bred CBir1 TCR transgenic (CBir1Tg) mice (specific to flagellin from common intestinal bacteria) onto a lymphopenic Rag1-/- background. Surprisingly, T cells from CBir1Tg mice bred onto a Rag1-/- background could not induce colitis and did not differentiate to become effectors under lymphopenic conditions, despite deficits in immunoregulatory factors, such as IgA, regulatory T cells, and type 3 innate lymphoid cells. In fact, upon transfer of conventional CBir1Tg T cells into lymphopenic mice, the vast majority of proliferating T cells responded to Ags other than CBir1 flagellin, including those found on other bacteria, such as Helicobacter spp. Thus, we discovered a caveat in the CBir1Tg model within our animal facility that illustrates the limitations of using TCR transgenics at mucosal surfaces, where multiple TCR specificities can respond to the plethora of foreign Ags. Our findings also indicate that T cell specificity to the microbiota alone is not sufficient to induce T cell activation and colitis. Instead, other interrelated factors, such as the composition and ecology of the intestinal microbiota and host access to Ag, are paramount in controlling the activation of microbiota-specific T cell clones.
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Affiliation(s)
- Pailin Chiaranunt
- Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224.,Department of Pediatrics, University of Pittsburgh Medical School, Pittsburgh, PA 15224
| | - Justin T Tometich
- Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224.,Department of Pediatrics, University of Pittsburgh Medical School, Pittsburgh, PA 15224
| | - Junyi Ji
- Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224.,Department of Pediatrics, University of Pittsburgh Medical School, Pittsburgh, PA 15224.,School of Medicine, Tsinghua University, Beijing 100084, China; and
| | - Timothy W Hand
- Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224; .,Department of Pediatrics, University of Pittsburgh Medical School, Pittsburgh, PA 15224.,Department of Immunology, University of Pittsburgh Medical School, Pittsburgh, PA 15213
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46
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Udden SMN, Peng L, Gan JL, Shelton JM, Malter JS, Hooper LV, Zaki MH. NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways. Cell Rep 2018; 19:2756-2770. [PMID: 28658623 DOI: 10.1016/j.celrep.2017.05.084] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 04/26/2017] [Accepted: 05/24/2017] [Indexed: 12/16/2022] Open
Abstract
Although NOD2 is the major inflammatory bowel disease susceptibility gene, its role in colorectal tumorigenesis is poorly defined. Here, we show that Nod2-deficient mice are highly susceptible to experimental colorectal tumorigenesis independent of gut microbial dysbiosis. Interestingly, the expression of inflammatory genes and the activation of inflammatory pathways, including NF-κB, ERK, and STAT3 are significantly higher in Nod2-/- mouse colons during colitis and colorectal tumorigenesis, but not at homeostasis. Consistent with higher inflammation, there is greater proliferation of epithelial cells in hyperplastic regions of Nod2-/- colons. In vitro studies demonstrate that, while NOD2 activates the NF-κB and MAPK pathways in response to MDP, it inhibits TLR-mediated activation of NF-κB and MAPK. Notably, NOD2-mediated downregulation of NF-κB and MAPK is associated with the induction of IRF4. Taken together, NOD2 plays a critical role in the suppression of inflammation and tumorigenesis in the colon via downregulation of the TLR signaling pathways.
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Affiliation(s)
- S M Nashir Udden
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lan Peng
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jia-Liang Gan
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - John M Shelton
- Molecular Pathology Core, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - James S Malter
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lora V Hooper
- Department of Immunology, UT Southwestern Medical Center, Dallas, TX 75390, USA; The Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Md Hasan Zaki
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
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47
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Pinheiro RO, Schmitz V, Silva BJDA, Dias AA, de Souza BJ, de Mattos Barbosa MG, de Almeida Esquenazi D, Pessolani MCV, Sarno EN. Innate Immune Responses in Leprosy. Front Immunol 2018; 9:518. [PMID: 29643852 PMCID: PMC5882777 DOI: 10.3389/fimmu.2018.00518] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 02/27/2018] [Indexed: 12/20/2022] Open
Abstract
Leprosy is an infectious disease that may present different clinical forms depending on host immune response to Mycobacterium leprae. Several studies have clarified the role of various T cell populations in leprosy; however, recent evidences suggest that local innate immune mechanisms are key determinants in driving the disease to its different clinical manifestations. Leprosy is an ideal model to study the immunoregulatory role of innate immune molecules and its interaction with nervous system, which can affect homeostasis and contribute to the development of inflammatory episodes during the course of the disease. Macrophages, dendritic cells, neutrophils, and keratinocytes are the major cell populations studied and the comprehension of the complex networking created by cytokine release, lipid and iron metabolism, as well as antimicrobial effector pathways might provide data that will help in the development of new strategies for leprosy management.
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Affiliation(s)
- Roberta Olmo Pinheiro
- Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Veronica Schmitz
- Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | | | - André Alves Dias
- Cellular Microbiology Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | | | | | | | | | - Euzenir Nunes Sarno
- Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
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48
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Kale SD, Dikshit N, Kumar P, Balamuralidhar V, Khameneh HJ, Bin Abdul Malik N, Koh TH, Tan GGY, Tan TT, Mortellaro A, Sukumaran B. Nod2 is required for the early innate immune clearance of Acinetobacter baumannii from the lungs. Sci Rep 2017; 7:17429. [PMID: 29234083 PMCID: PMC5727160 DOI: 10.1038/s41598-017-17653-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 11/19/2017] [Indexed: 12/19/2022] Open
Abstract
Acinetobacter baumannii (A. baumannii) is a significant cause of severe nosocomial pneumonia in immunocompromised individuals world-wide. With limited treatment options available, a better understanding of host immnity to A. baumannii infection is critical to devise alternative control strategies. Our previous study has identified that intracellular Nod1/Nod2 signaling pathway is required for the immune control of A. baumannii in airway epithelial cells in vitro. In the current study, using Nod2−/− mice and an in vivo sublethal model of pulmonary infection, we show that Nod2 contributes to the early lung defense against A. baumannii infection through reactive oxygen species (ROS)/reactive nitrogen species (RNS) production as Nod2−/− mice showed significantly reduced production of ROS/RNS in the lungs following A. baumannii infection. Consistent with the higher bacterial load, A. baumannii-induced neutrophil recruitment, cytokine/chemokine response and lung pathology was also exacerbated in Nod2−/− mice at early time points post-infection. Finally, we show that administration of Nod2 ligand muramyl dipeptide (MDP) prior to infection protected the wild- type mice from A. baumannii pulmonary challenge. Collectively, Nod2 is an important player in the early lung immunity against A. baumannii and modulating Nod2 pathway could be considered as a viable therapeutic strategy to control A. baumannii pulmonary infection.
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Affiliation(s)
- Sandeep D Kale
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Neha Dikshit
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Pankaj Kumar
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, 169857, Singapore
| | | | - Hanif Javanmard Khameneh
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Singapore
| | - Najib Bin Abdul Malik
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Tse Hsien Koh
- Department of Microbiology, Division of Pathology, Singapore General Hospital, Singapore, Singapore
| | | | - Thuan Tong Tan
- Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore
| | - Alessandra Mortellaro
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Singapore
| | - Bindu Sukumaran
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, 169857, Singapore.
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49
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Holzer P, Farzi A, Hassan AM, Zenz G, Jačan A, Reichmann F. Visceral Inflammation and Immune Activation Stress the Brain. Front Immunol 2017; 8:1613. [PMID: 29213271 PMCID: PMC5702648 DOI: 10.3389/fimmu.2017.01613] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 11/07/2017] [Indexed: 12/20/2022] Open
Abstract
Stress refers to a dynamic process in which the homeostasis of an organism is challenged, the outcome depending on the type, severity, and duration of stressors involved, the stress responses triggered, and the stress resilience of the organism. Importantly, the relationship between stress and the immune system is bidirectional, as not only stressors have an impact on immune function, but alterations in immune function themselves can elicit stress responses. Such bidirectional interactions have been prominently identified to occur in the gastrointestinal tract in which there is a close cross-talk between the gut microbiota and the local immune system, governed by the permeability of the intestinal mucosa. External stressors disturb the homeostasis between microbiota and gut, these disturbances being signaled to the brain via multiple communication pathways constituting the gut-brain axis, ultimately eliciting stress responses and perturbations of brain function. In view of these relationships, the present article sets out to highlight some of the interactions between peripheral immune activation, especially in the visceral system, and brain function, behavior, and stress coping. These issues are exemplified by the way through which the intestinal microbiota as well as microbe-associated molecular patterns including lipopolysaccharide communicate with the immune system and brain, and the mechanisms whereby overt inflammation in the GI tract impacts on emotional-affective behavior, pain sensitivity, and stress coping. The interactions between the peripheral immune system and the brain take place along the gut-brain axis, the major communication pathways of which comprise microbial metabolites, gut hormones, immune mediators, and sensory neurons. Through these signaling systems, several transmitter and neuropeptide systems within the brain are altered under conditions of peripheral immune stress, enabling adaptive processes related to stress coping and resilience to take place. These aspects of the impact of immune stress on molecular and behavioral processes in the brain have a bearing on several disturbances of mental health and highlight novel opportunities of therapeutic intervention.
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Affiliation(s)
- Peter Holzer
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.,BioTechMed-Graz, Graz, Austria
| | - Aitak Farzi
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Ahmed M Hassan
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Geraldine Zenz
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Angela Jačan
- CBmed GmbH-Center for Biomarker Research in Medicine, Graz, Austria
| | - Florian Reichmann
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
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Lee JY, Lee MS, Kim DJ, Yang SJ, Lee SJ, Noh EJ, Shin SJ, Park JH. Nucleotide-Binding Oligomerization Domain 2 Contributes to Limiting Growth of Mycobacterium abscessus in the Lung of Mice by Regulating Cytokines and Nitric Oxide Production. Front Immunol 2017; 8:1477. [PMID: 29163541 PMCID: PMC5681718 DOI: 10.3389/fimmu.2017.01477] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2017] [Accepted: 10/20/2017] [Indexed: 12/22/2022] Open
Abstract
Mycobacterium abscessus is a prominent cause of pulmonary infection in immunosuppressed patients and those with cystic fibrosis. Nucleotide-binding oligomerization domain (NOD) 2 is a cytosolic receptor which senses a bacterial peptidoglycan component, muramyl dipeptide (MDP). Although nucleotide-binding oligomerization domain 2 (NOD2) contributes to protect host against various microbial infections, it is still unclear whether NOD2 is essential to regulate host immune responses against M. abscessus infection. In this study, we sought to clarify the role of NOD2 and the underlying mechanism in host defense against M. abscessus infection. Mice were infected intranasally with M. abscessus and sacrificed at indicated time points. Bacterial survival, cytokines production, and pathology in the lungs were determined. Bone marrow-derived macrophages were used to clarify cellular mechanism of NOD2-mediated immune response. Bacterial clearance was impaired, and pathology was more severe in the lungs of NOD2-deficient mice compared with the wild-type mice. In macrophages, NOD2-mediated activation of p38 and JNK were required for production of proinflammatory cytokines and nitric oxide (NO) and expression of iNOS in response to M. abscessus. NO was critical for limiting intracellular growth of the pathogen. Intranasal administration of MDP reduced in vivo bacterial replication and thus improved lung pathology in M. abscessus-infected mice. This study offers important new insights into the potential roles of the NOD2 in initiating and potentiating innate immune response against M. abscessus pulmonary infection.
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Affiliation(s)
- Jun-Young Lee
- Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
| | - Moo-Seung Lee
- Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Dong-Jae Kim
- Laboratory Animal Resource Center, Daegu Gyeongbuk Institute of Science & Technology (DGIST), Daegu, South Korea
| | - Soo-Jin Yang
- School of Bioresources and Bioscience, Chung-Ang University, Anseong, South Korea
| | - Sang-Jin Lee
- Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
| | - Eui-Jeong Noh
- Department of Obstetrics and Gynecology, College of Medicine, Konyang University, Daejeon, South Korea
| | - Sung Jae Shin
- Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Jong-Hwan Park
- Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
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