Functional defects in NOD2 signaling in experimental and human Crohn disease

Corridoni, Daniele; Arseneau, Kristen O.; Cominelli, Fabio

doi:10.4161/gmic.28404

Cited by 18 publications

(19 citation statements)

References 47 publications

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“…The identification of NOD2 generated a fundamental shift in understanding CD pathogenesis, with a new focus on mechanisms of innate immunity and host-microbial interactions within the gut. Interestingly, NOD2 genetic deletion in SAMP1/YitFc mice significantly suppresses chronic ileitis by approximately 50%, 54 supporting the concept of a dichotomous role of NOD2 in early vs late (chronic) phases of intestinal inflammation 47 …”

Section: Pathogenic Mechanisms Of Crohn’s-like Ileitismentioning

confidence: 86%

“…SAMP1/YitFc and Tnf ΔARE/+ mice develop Crohn’s-like ileitis in the absence of spontaneous colonic inflammation, making them very useful models to study the contribution of mucosal healing in the presence of immunologic and genetic dysfunction, independent of active colonic inflammation. In fact, Corridoni et al 47 recently showed that induction of acute colitis by DSS administration in SAMP1/YitFc mice generated more severe and prolonged colitis compared with AKR control mice, suggesting that mucosal healing and impaired resolution of inflammation may be important in this model. Further studies are warranted to determine the precise potential dysfunction of mucosal healing in both models and its contribution to the pathogenesis of IBD.…”

Section: Pathogenic Mechanisms Of Crohn’s-like Ileitismentioning

confidence: 99%

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Uncovering Pathogenic Mechanisms of Inflammatory Bowel Disease Using Mouse Models of Crohn’s Disease–Like Ileitis: What is the Right Model?

Cominelli

Arseneau

Rodriguez-Palacios

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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Crohn’s disease and ulcerative colitis, together known as inflammatory bowel disease, are debilitating chronic disorders of unknown cause and cure. Our evolving understanding of these pathologies is enhanced greatly by the use of animal models of intestinal inflammation that allow in vivo mechanistic studies, preclinical evaluation of new therapies, and investigation into the causative factors that underlie disease pathogenesis. Several animal models, most commonly generated in mice, exist for the study of colitis. The appropriateness of their use often can be determined by their mode of generation (ie, chemical induction, T-cell transfer, targeted genetic manipulation, spontaneously occurring, and so forth), the type of investigation (mechanistic studies, pathogenic experiments, preclinical evaluations, and so forth), and the type of inflammation that occurs in the model (acute vs chronic colitis, tissue injury/repair, and so forth). Although most murine models of inflammatory bowel disease develop inflammation in the colon, Crohn’s disease most commonly occurs in the terminal ileum, where a very limited number of mouse models manifest disease. This review discusses appropriate experimental applications for different mouse models of colitis, and highlights the particular utility of 2 highly relevant models of Crohn’s-like ileitis—the spontaneous SAMP1/YitFc inbred mouse strain and the genetically engineered TnfΔAU-rich element/+ mouse model of tumor necrosis factor overexpression, both of which bear strong resemblance to the human condition. Similar to patients with Crohn’s disease, SAMP1/YitFc ileitis develops spontaneously, without chemical, genetic, or immunologic manipulation, making this model particularly relevant for studies aimed at identifying the primary defect underlying the occurrence of Crohn’s ileitis, as well as preclinical testing of novel treatment modalities.

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Section: Pathogenic Mechanisms Of Crohn’s-like Ileitismentioning

confidence: 86%

Section: Pathogenic Mechanisms Of Crohn’s-like Ileitismentioning

confidence: 99%

Uncovering Pathogenic Mechanisms of Inflammatory Bowel Disease Using Mouse Models of Crohn’s Disease–Like Ileitis: What is the Right Model?

Cominelli

Arseneau

Rodriguez-Palacios

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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“…NLRs are broadly classified as those that activate "proinflammatory" transcription factors and cytokine production (e.g., NF-κB) and those that mediate assembly and activation of the inflammasome (described below). NOD2, the first identified and still most prominent IBD susceptibility gene, is an example for the former group of NLRs, with critical, but still not completely clear, roles in regulation of host defence and immune homeostasis in the gut (Corridoni et al 2014).…”

Section: Innate Immunity and Host Defence: Bridging Between The Host mentioning

confidence: 99%

Host–microbe interactions in the gut: lessons learned from models of inflammatory bowel diseases

WineEytan

2014

LymphoSign Journal

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The mammalian gut is the richest immune organ in the body and serves as a central location for immune system development, processing, and education. Inflammatory bowel diseases (IBD) provide excellent models for studying both innate and adaptive responses to gut microbes and the host-immune system – microbe interactions in the gut. Microbes are linked to almost all of the known disease-associated genetic polymorphisms in IBD and are critical mediators of environmental effects (through food, hygiene, and infection). Human and animal-based research supports the central role of microbes in IBD pathogenesis at multiple levels. Animal models of IBD only develop in the presence of microbes, and co-housing mice that are genetically susceptible to gut inflammation with normal mice can lead to the development of bowel injury. Recent advances in research technologies, such as deep-sequencing that enables detailed compositional analyses, have revolutionized the study of host–microbe interactions in the gut; however, knowing which bacteria are present in the bowel is likely not sufficient. The function of the microbiota as a community is recognized as a critical factor for gut homeostasis. Animal models of IBD have provided critical insight into basic biology and disease pathogenesis, especially regarding the role of microbes in IBD pathogenesis. Although many of these recent discoveries on host–microbe interactions are not yet applied to patient care, these basic observations will certainly revolutionize patient care in the future. Using such data, we may be able to predict risk of disease, define biological subtypes, establish tools for prevention, and even cure IBD using microbes or their products. A broad spectrum of therapeutic tools spanning from fecal transplantation, probiotics, prebiotics, and microbial products to microbe-tailored diets may supplement current IBD treatments.

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“…Pattern recognition receptors (PRRs) recognize foreign antigen to direct innate and adaptive immune responses against invading pathogens (1). Polymorphisms in the PRR nucleotide-binding oligomerization domain-containing protein 2 (NOD2) represent the strongest genetic risk factor for the inflammatory bowel disease Crohn's (CD), and thus this bacterial sensor is the focus of particular research interest (2)(3)(4). NOD2 recognizes muramyl dipeptide (MDP), the largest fraction of peptidoglycan, that is present in the cell walls of all bacteria (5).…”

Section: Introductionmentioning

confidence: 99%

Ataxin-3 links NOD2 and TLR2 mediated innate immune sensing and metabolism in myeloid cells

Chapman

Corridoni

Shiraishi

et al. 2019

Preprint

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The interplay between NOD2 and TLR2 following recognition of components of the bacterial cell wall peptidoglycan is well established, however their role in redirecting metabolic pathways in myeloid cells to degrade pathogens and mount antigen presentation remains unclear. We show NOD2 and TLR2 mediate phosphorylation of the deubiquitinase ataxin-3 via RIPK2 and TBK1. In myeloid cells ataxin-3 associates with the mitochondrial cristae protein MIC60, and is required for oxidative phosphorylation. Depletion of ataxin-3 leads to impaired induction of mitochondrial reactive oxygen species (mROS) and defective bacterial killing. A mass spectrometry analysis of NOD2/TLR2 triggered ataxin-3 deubiquitination targets revealed immunometabolic regulators, including HIF-1α and LAMTOR1 that may contribute to these effects. Thus, we define how ataxin-3 plays an essential role in NOD2 and TLR2 sensing and effector functions in myeloid cells. Significance StatementIn recent years it has become clear that cross-talk between metabolic and immune pathways is central to the regulation of host defence. This interplay appears of particular importance in myeloid cells including dendritic cells and macrophages, but it is unclear how two of their key bacterial sensors NOD2 and TLR2 influence metabolism. Here, we define how NOD2/TLR2 signal in myeloid cells to drive optimal mitochondrial functioning required for bacterial destruction. We uncover a new role for Ataxin-3, a deubiquitinase required for non-selective autophagy, in this pathway.We provide a non-biased analysis of Ataxin-3 targets generating evidence for a role in deubiquitination of metabolic mediators during myeloid cell differentiation that will provide an important basis for further study.

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Functional defects in NOD2 signaling in experimental and human Crohn disease

Cited by 18 publications

References 47 publications

Uncovering Pathogenic Mechanisms of Inflammatory Bowel Disease Using Mouse Models of Crohn’s Disease–Like Ileitis: What is the Right Model?

Uncovering Pathogenic Mechanisms of Inflammatory Bowel Disease Using Mouse Models of Crohn’s Disease–Like Ileitis: What is the Right Model?

Host–microbe interactions in the gut: lessons learned from models of inflammatory bowel diseases

Ataxin-3 links NOD2 and TLR2 mediated innate immune sensing and metabolism in myeloid cells

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