Examining the Role of NLRP3 in Intestinal Homeostasis and Fibrosis
Date
2018-07-24
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Abstract
Fibrosis is the most common cause of surgery in Crohn’s disease (CD) and the mechanisms of fibrosis in CD are not well understood. Nucleotide-binding oligomerization domain (NOD)-like receptors, including NLRP3, are cytosolic protein sensors involved in inflammatory pathways and implicated in CD pathogenesis. NLRP3 has been shown to drive fibrosis in various tissues, including the heart, kidney, lungs, liver and pancreas; however, its role in intestinal fibrosis is currently unknown. The main hypothesis of this project is that NLRP3 mediates intestinal fibrosis. Primary intestinal myofibroblasts isolated from Nlrp3-/- mice had reduced response to pro-fibrogenic cytokine TGFβ compared to wildtype (WT), with lower phosphorylation of downstream signalling protein Smad2, and decreased induction of connective tissue growth factor (CTGF), as well as decreased migration. Loss of NLRP3 in intestinal myofibroblasts also led to increased resistance to cell death during serum deprivation. In an in vivo model of chronic colitis, Nlrp3-/- mice had significantly worse disease and susceptibility compared to WT. However, both Nlrp3-/- and WT mice had similar levels of intestinal fibrosis. Relevance to the human disease was further highlighted by the finding that NLRP3 transcript levels in mucosal colonic biopsies from patients with CD were significantly increased, and increased expression correlated with inflammation. Overall, our data suggest that loss of NLRP3 leads to reduced response to TGFβ in colonic myofibroblasts, and that NLRP3 may potentiate TGFβ beta signalling in the gut. Further insights into the mechanisms of intestinal fibrosis will significantly impact the development of new tools that will help with assessing and treating patients with CD complications.
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Keywords
Inflammation, fibrosis, inflammasome, Crohn's disease, inflammatory bowel disease
Citation
Tjong, J. R. (2018). Examining the Role of NLRP3 in Intestinal Homeostasis and Fibrosis (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/32695