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RNA-seq of intestinal epithelial cells isolated from DSS colitis model mice

ABSTRACT: In the present study, we demonstrated that mice deficient in chemerin or IEC-specific CMKLR1 expression were highly susceptible to DSS-induced colitis and subsequent tumorigenesis, which was reversed by suppressing colonic neutrophilic inflammation using CXCR2 inhibitor. Surprisingly, we found that lack of the Chemerin-CMKLR1 signaling specifically reduced colonic epithelial expression of lactoperoxidase (LPO), an epithelial peroxidase which could utilize H2O2 to oxidase thiocyanates to antibiotic compound (Bafort et al., 2014). Importantly, we demonstrated that impaired epithelial LPO expression accounted for outgrowth of potentially pathogenic Gram-negative bacteria following epithelial injury, which led to overproduction of CXCL1/2 and pathological neutrophilic inflammation in mice with epithelial Chemerin-CMKLR1 signaling deficiency. Finally, lack of epithelial Chemerin-CMKLR1 signaling impaired early host defense against enteric bacteria, which was reversed by LPO supplementation. Taken together, our study uncovers a critical role of epithelial Chemerin-CMKLR1 signaling in restricting pathological colonic neutrophilia via potentiating LPO-mediated epithelial innate defense, thereby rendering protection against microbiota-driven colitis and tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE178308 | GEO | 2022/06/30

REPOSITORIES: GEO

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Project description:Leber2015 - Mucosal immunity and gut microbiome interaction during C. difficile infection This model is described in the article: Systems Modeling of Interactions between Mucosal Immunity and the Gut Microbiome during Clostridium difficile Infection. Leber A, Viladomiu M, Hontecillas R, Abedi V, Philipson C, Hoops S, Howard B, Bassaganya-Riera J. PLoS ONE 2015; 10(7): e0134849 Abstract: Clostridium difficile infections are associated with the use of broad-spectrum antibiotics and result in an exuberant inflammatory response, leading to nosocomial diarrhea, colitis and even death. To better understand the dynamics of mucosal immunity during C. difficile infection from initiation through expansion to resolution, we built a computational model of the mucosal immune response to the bacterium. The model was calibrated using data from a mouse model of C. difficile infection. The model demonstrates a crucial role of T helper 17 (Th17) effector responses in the colonic lamina propria and luminal commensal bacteria populations in the clearance of C. difficile and colonic pathology, whereas regulatory T (Treg) cells responses are associated with the recovery phase. In addition, the production of anti-microbial peptides by inflamed epithelial cells and activated neutrophils in response to C. difficile infection inhibit the re-growth of beneficial commensal bacterial species. Computational simulations suggest that the removal of neutrophil and epithelial cell derived anti-microbial inhibitions, separately and together, on commensal bacterial regrowth promote recovery and minimize colonic inflammatory pathology. Simulation results predict a decrease in colonic inflammatory markers, such as neutrophilic influx and Th17 cells in the colonic lamina propria, and length of infection with accelerated commensal bacteria re-growth through altered anti-microbial inhibition. Computational modeling provides novel insights on the therapeutic value of repopulating the colonic microbiome and inducing regulatory mucosal immune responses during C. difficile infection. Thus, modeling mucosal immunity-gut microbiota interactions has the potential to guide the development of targeted fecal transplantation therapies in the context of precision medicine interventions. This model is hosted on BioModels Database and identified by: BIOMD0000000583. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:BACKGROUND & AIMS: Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition driven by loss of homeostasis between the mucosal immune system, the commensal gut microbiota, and the intestinal epithelium. Our overarching goal is to understand how these components of the intestinal ecosystem cooperate to control homeostasis and to identify novel signal transduction pathways that become dysregulated in IBD. METHODS: We have applied a multi-scale systems biology approach to a mouse model of chronic colitis. We combined quantitative measures of epithelial hyperplasia and immune infiltration with multivariate analysis of inter- and intra-cellular signaling molecules in order to generate a tissue level model of the inflamed disease state. We utilized the computational model to identify signaling pathways that were dysregulated in the context of colitis and then validated model predictions by measuring the effect of small molecule pathway inhibitors on colitis. RESULTS: Our data-driven computational model identified mTOR signaling as a potential driver of inflammation and mTOR inhibition reversed the molecular, immunological, and epithelial manifestations of colitis. Inhibition of Notch signaling, which induces epithelial differentiation, had the same effect, suggesting that the epithelial proliferation/differentiation state plays a key role in maintaining homeostasis of the colon. Confirming this, we found that colonic organoids grown ex vivo showed a similar relationship between proliferation and cytokine expression, even in the absence of gut bacteria and immune cells. CONCLUSIONS: Our study provides a tissue-level systems biology perspective of murine colitis and suggests that mTOR plays a key role in regulating colonic homeostasis by controlling epithelial proliferation/differentiation state. We used microarrays to examine changes in global gene expression patterns associated with chronic inflammation induced by the T cell transfer model of Inflammatory Bowel Disease.

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RNA-seq of intestinal epithelial cells isolated from DSS colitis model mice

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