DOP90 The role of Nlrp9b, a novel NLR member in regulating experimental colitis
D. Zheng1,2, M. Levy1, E. Elinav1
1Immunology Department, Weizmann Institute of Science, Rehovot, Israel, 2Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
The NOD-like receptors (NLR) are important family members of the intracellular pathogen recognition receptors, which recognise pathogen- or danger-associated molecular patterns in the cell. The NLR signalling pathways are increasingly recognised to play critical roles in the pathogenesis of inflammatory bowel diseases. We have identified an NLR member, Nlrp9b, whose expression is restricted to the epithelium of the gastrointestinal tract. However, the role of Nlrp9b in regulating intestinal inflammation and the underlying mechanism remains to be clarified.
We generated constitutive Nlrp9b-deficient (Nlrp9b−/−) mice to study the function of Nlrp9b. We induced experimental colonic inflammation by using dextran sulphate sodium (DSS). Bone marrow transfer experiments were conducted to clarify the cell type in which Nlrp9b exerts its function. We then performed RNA-sequencing of intestinal tissues from Nlrp9b−/− mice and WT controls to investigate the potential mechanisms.
Nlrp9b−/− mice were more susceptible to DSS-induced colitis compared with cohousing wild-type (WT) mice, manifesting as exacerbated weight loss, more severe inflammation in colonoscopy and histopathology. Non-haematopoietic expression of Nlrp9b was responsible for protection against intestinal inflammation. Inflammasome activation was not impaired in Nlrp9b−/− mice, as we detected no defects in both cleavage of caspase 1 and secretion of IL18 in Nlrp9b−/− mice. Through RNA sequencing, we identified 300 differentially expressed genes in the intestinal tissue between Nlrp9b−/− and the co-housed WT controls, which primarily belongs to pathways involved in intestinal IgA production, as well as antigen processing and presentation. Indeed, IgA levels were globally reduced in Nlrp9b−/− mice, on the levels of mRNA expression, secreted antibodies measured in the intestinal lumen, and serum IgA. Furthermore, the total numbers of immune cells in the Peyer's patches were significantly reduced in Nlrp9b−/− mice, including leukocytes, B cells and B cells in the germinal centres, where they class switch to IgA producing cells.
Nlrp9b functions in the non-haematopoietic compartments of intestine and is protective against experimental intestinal inflammation, through potential mechanisms involving intestinal IgA production.