Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic challenges

Abstract

Bacterial flagellin is a dominant innate immune activator of the intestine. Therefore, we examined the role of the intracellular flagellin receptor, NLRC4, in protecting the gut and/or driving inflammation. In accord with NLRC4 acting via transcription-independent pathways, loss of NLRC4 did not reduce the rapid robust changes in intestinal gene expression induced by flagellin administration. Loss of NLRC4 did not alter basal intestinal homeostasis nor predispose mice to development of colitis upon administration of an anti-IL-10R monoclonal antibody. However, epithelial injury induced by dextran sulfate sodium (DSS) in mice lacking NLRC4 resulted in more severe disease indicating a role for NLRC4 in protecting the gut. Moreover, loss of NLRC4 resulted in increased mortality in response to flagellate, but not aflagellate Salmonella infection. Thus, despite not being involved in rapid intestinal gene remodeling upon detection of flagellin, NLRC4-mediated inflammasome activation results in production of IL-1β and IL-18, two cytokines that protect mice from mucosal and systemic challenges.

Inflammasomes

“…Both NLRP3 and NLRC4 were shown to detect S. typhimurium (Broz et al , 2012Carvalho et al 2012), and IL-1b and IL-18 were found to be important for controlling S. typhimurium infection (Raupach et al 2006). Similar to S. typhimurium, C. rodentium infection results in NLRP3-and NLRC4-dependent inflammatory responses that limit bacterial burden and tissue pathology, which was proposed to be IL-18 dependent (Kayagaki et al 2011b;Gurung et al 2012b;Liu et al 2012a;Alipour et al 2013).…”

Epithelial NAIPs protect against colonic tumorigenesis

“…However, whether they act as IAPs is controversial. Additionally, NAIPs belong to the NLR family, and several NLRs are protective in colonic inflammation and tumorigenesis, through a variety of mechanisms (Allen et al, 2010;Hu et al, 2010;Chen et al, 2011;Elinav et al, 2011;Zaki et al, 2011;Carvalho et al, 2012). Naip1-6 fl/fl and Naip1-6 / mice (nonlittermates) were challenged in a CAC model with administration of the carcinogen azoxymethane (AOM; 10 mg/kg) followed by three cycles of dextran sulfate sodium (DSS; 2.5% wt/vol) to induce colitis and accelerate tumorigenesis.…”

Activation of NLRC4 downregulates TLR5-mediated antibody immune responses against flagellin

“…For example, TLR5-deficient mice are less prone to infection with Salmonella than are wild-type (WT) mice, 19 and NLRC4 activation might protect mice from the mucosal and systemic dissemination of salmonella. 20 But, Letran et al observed no significant difference in the susceptibility of mice to bacterial infection in WT and TLR5-deficient mice. 21 On the other hand, Salmonella could downregulate NLRC4 expression to prevent the inflammasome response and thereby promote bacterial persistence and dissemination.…”