ECCO Fellowship Study Synopsis: Danping Zheng
Danping Zheng, ECCO Fellow 2018
The role of Nlrp9b in regulating intestinal inflammation
© Danping Zheng
Aim of the research
Innate immune signalling pathways, including inflammasome-forming Noll-like receptors (NLR), are thought to mediate the risk of Inflammatory Bowel Disease (IBD) since this system acts as the first line of defence in the recognition of enteric pathogens. In our preliminary study, we identified a new NLR member, Nlrp9b, whose role in the pathogenesis of IBD remains to be clarified. The aim of our study is to investigate the role of Nlrp9b in regulating intestinal inflammation and the underlying mechanisms.
We found that Nlrp9b gene expression is restricted to the gastrointestinal tract. We then generated conditional Nlrp9b-deficient (Nlrp9b-/-) mice to study its function. Nlrp9b-/- mice were more susceptible to dextran sodium sulphate (DSS)-induced colitis compared with co-housing wild type (WT) mice, this susceptibility manifesting as exacerbated weight loss and higher colonoscopy and histopathological scores. Next we sought to clarify the cell type where Nlrp9b functions by means of bone marrow transfer experiments. Expression of Nlrp9b was detectable only in the non-haematopoietic compartment in the gastrointestinal tract. Consistently, high expression was found in the sorted intestinal EpCAM+ cells but not in CD45+ cells, indicating that the expression was limited to the epithelial compartment. Notably, mice lacking Nlrp9b in the non-haematopoietic compartment displayed enhanced susceptibility to DSS-induced colitis, with more weight loss, higher mortality and more severe colonic inflammation. In future studies, we will decipher potential mechanisms underlying Nlrp9b’s protection against intestinal inflammation, including inflammasome activation and modulation of intestinal microbiota.
First quarter: confirmation of the phenotypic consequences under littermate controlled conditions. Second quarter: Investigation of the downstream signals of the Nlrp9b inflammasome. Third quarter: Identification of the role of Nlrp9b in regulating host–microbiota interaction. Fourth quarter: Completion of data analysis and preparation of the manuscript.