Dissecting NOD2 inflammatory signaling in a Blau syndrome model 9380

Abstract Description NOD2 is an intracellular receptor for bacterial components such as MDP, activating inflammatory responses via RIP2-dependent NF-κB and MAPK pathways. Mutations in NOD2 are linked to various inflammatory diseases, including Crohn’s disease and Blau syndrome. To investigate NOD2-RIP2 signaling in Blau syndrome, we developed NOD2-R307W knock-in (KI) mice, which mimic the mutation observed in Blau syndrome patients. NOD2-R307W KI mice did not exhibit spontaneous inflammation and there were no differences in gene expression between wild-type (WT) and KI mice. Macrophages from KI mice exhibited normal NOD2 protein levels and basal cytokine expression. In addition, KI mice were protected against Listeria infection, achieving survival rates comparable to WT mice. Interestingly, in a murine inflammation model, MDP plus LPS treatment caused elevated TNF, IL-6, and IFN-γ levels in KI mice, compared to WT and NOD2 knockout (KO) mice. Cells expressing either WT or NOD2 disease variants exhibited comparable NF-κB activation upon MDP stimulation, which was blocked by RIP2 inhibitors. Importantly, LPS+MDP stimulation resulted in similar TNF and CCL3 expression in macrophages from WT and KI mice, and RIP2 inhibitors efficiently attenuated cytokine levels. The ability of RIP2 inhibitors to block NF-κB pathway induced by NOD2 variants associated with inflammatory diseases suggests their potential to ameliorate symptoms in patients with immune conditions reliant on NOD2-mediated signaling. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)