NLRP3 inflammasome remains controversial with both protective and harmful effects reported in experimental colitis and colitis associated colorectal cancer (CAC) murine models. To address this controversy, we designed the world first murine model deficient in NLRP3 in a spontaneous chronic colitis mouse model Winnie1. Our results of WinniexNlrp3−/− at 12 and 16 weeks, shows spontaneous multiple colonic tumours with significant colonic shortening, increased activity of myeloperoxidase, Nitric Oxide and serum C-reactive protein. Histopathology revealed high-grade dysplasia and adenocarcinoma regions with increased DNA damage, oxidative stress, Ki-67, VEGF and Survivin biomarkers. Colon tissue culture supernatants identified differential expression of cytokines and chemokines. Protein analysis of colonic tumours showed upregulation of Wnt/β-catenin and PI3K/ AKT pathways while qPCR identified upregulation of CAC biomarkers. Faecal microbiota analysis revealed significant increase in colitogenic members in the phylogenetic architecture in WinniexNlrp3−/− mice while metabolomics profiling revealed upregulation of key metabolites and short chain fatty acids. In addition, we looked at the therapeutic effect of specific small molecule NLRP3 inhibitor, MCC950 in Winnie mice. Oral administration of MCC950 significantly improved colonic length, disease activity index, histopathology and significantly reduced proinflammatory cytokines ameliorating colitis 2 .Our results show genetic ablation of NLRP3 gene in a chronic colitis model lead to CAC. However, chemical inhibition of an overactive NLRP3 inflammasome in chronic colitis attenuates severity of the disease. Altogether our results stresses the need for careful investigation of temporal therapeutic strategies for NLRP3 inhibitors in the gut at different disease phases in clinically relevant experimental models.
References
1. Heazlewood, C. K. et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. 5, e54 (2008).
2. Perera, A. P. et al. MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice. Scientific Reports. 8, 8618 (2018).
