Regulatory processes in mucosal homeostasis

Abstract

The gastrointestinal tract is a paradox: while there are multiple defense mechanisms to protect against infection by luminal microbes, immune tolerance against commensal microbes must be constitutively maintained. In these complex tissues, epithelial, immune, and stromal cells promote mucosal homeostasis by actively responding to microbial components and metabolites. Any breach of the epithelial barrier drives microbes into contact with immune cells, resulting in inflammation. When uncontrolled, chronic diseases, such as inflammatory bowel disease (IBD), can develop with severe manifestations associated with fibrosis. While mucosal homeostasis is impacted by genetics, environment, and microbiome, there still remains much to learn with respect to signaling pathways and cellular heterogeneity that promote this equilibrium. We expand on current knowledge regarding regulatory processes controlling mucosal homeostasis, with a focus on mechanistic regulation of phagocyte-driven inflammation and the impact of chronic inflammation on stromal cells and fibrosis. Upon microbial exposure, phagocytes produce nitric oxide (NO) to combat microbial infection. How host tissues deal with this oxidative stress and how NO impacts inflammatory signaling are incompletely understood. We identify an NO-mediated antioxidant response as a negative feedback regulator of inflammation. Upon TLR stimulation, reactive nitrogen intermediates induce Nrf2-dependent antioxidant genes, including Prdx5. Engaging the antioxidant response is sufficient to suppress cytokine production, and Prdx5 is required for attenuation of cytokine production. Collectively, these findings delineate the reciprocal regulation of inflammation and cellular redox systems in phagocytes. In the face of chronic inflammation, mucosal tissues can develop fibrosis, which is a complication of IBD that is untreatable. Identifying the full stromal heterogeneity in the colon, as well as identifying molecular circuits driving fibrosis, is imperative to provide insight into the relationship between inflammation, fibrosis and healing. We used single cell profiling to characterize mucosal stromal heterogeneity, identifying Adamdec1 as a key feature of fibroblast-to-myofibroblast differentiation that is required for submucosal matrix remodeling and healing after inflammation. Together, we identify cellular and molecular mechanisms bridging innate inflammatory pathways in phagocytes and fibrotic pathways in mucosal stromal cells. These results contribute novel insights into regulatory processes mediating mucosal homeostasis.