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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and
T Watanabe1, N Asano2, G Meng3
11] Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan [2] Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA [3] Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Abstract:
It is well established that polymorphisms of the caspase activation and recruitment domain 15 (CARD15) gene, a major risk factor in Crohn's disease (CD), lead to loss of nucleotide-binding oligomerization domain 2 (NOD2) function. However, a molecular explanation of how such loss of function leads to increased susceptibility to CD has remained unclear. In a previous study exploring this question, we reported that activation of NOD2 in human dendritic cells by its ligand, muramyl dipeptide (MDP), negatively regulates Toll-like receptor (TLR)-mediated inflammatory responses. Here we show that NOD2 activation results in increased interferon regulatory factor 4 (IRF4) expression and binding to tumor necrosis factor receptor associated factor 6 (TRAF6) and RICK (receptor interacting serine-threonine kinase). We then show that such binding leads to IRF4-mediated inhibition of Lys63-linked polyubiquitination of TRAF6 and RICK and thus to downregulation of nuclear factor (NF)-κB activation. Finally, we demonstrate that protection of mice from the development of experimental colitis by MDP or IRF4 administration is accompanied by similar IRF4-mediated effects on polyubiquitination of TRAF6 and RICK in colonic lamina propria mononuclear cells. These findings thus define a mechanism of NOD2-mediated regulation of innate immune responses to intestinal microflora that could explain the relation of CARD15 polymorphisms and resultant NOD2 dysfunction to CD.
Insights
Genetic variations in CARD15 increase Crohn's disease risk by impairing NOD2 function. This study reveals NOD2 activation regulates immune responses via IRF4, impacting NF-κB signaling and potentially explaining CD susceptibility.
Area of Science:
- Immunology
- Genetics
- Gastroenterology
Background:
- Polymorphisms in the CARD15 gene are a significant risk factor for Crohn's disease (CD), leading to impaired NOD2 function.
- The precise molecular mechanisms linking NOD2 dysfunction to increased CD susceptibility remain incompletely understood.
- Previous work indicated NOD2 activation negatively regulates TLR-mediated inflammation in dendritic cells.
Purpose of the Study:
- To elucidate the molecular mechanism by which NOD2 dysfunction contributes to Crohn's disease pathogenesis.
- To define the role of interferon regulatory factor 4 (IRF4) in NOD2-mediated immune regulation.
- To investigate the impact of NOD2 activation on inflammatory signaling pathways relevant to CD.
Main Methods:
- Investigated NOD2 activation by muramyl dipeptide (MDP) in human dendritic cells.
- Analyzed the interaction of NOD2-activated IRF4 with TRAF6 and RICK.
- Assessed the effect of IRF4 on Lys63-linked polyubiquitination of TRAF6 and RICK, and subsequent NF-κB activation.
- Utilized a mouse model of experimental colitis to evaluate the therapeutic potential of MDP or IRF4.
Main Results:
- NOD2 activation leads to increased IRF4 expression, which binds to TRAF6 and RICK.
- This binding inhibits Lys63-linked polyubiquitination of TRAF6 and RICK, downregulating NF-κB activation.
- Administration of MDP or IRF4 protected mice from experimental colitis, associated with similar IRF4-mediated effects on TRAF6/RICK polyubiquitination in colonic cells.
Conclusions:
- NOD2 activation regulates innate immune responses to gut microbiota through an IRF4-dependent mechanism.
- This pathway involves the modulation of TRAF6 and RICK polyubiquitination, impacting NF-κB signaling.
- Findings provide a molecular explanation for how CARD15 polymorphisms and NOD2 dysfunction increase Crohn's disease risk.
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