A Balanced IL-1β Activity Is Required for Host Response to Citrobacter rodentium Infection

Abstract

Microbial sensing plays essential roles in the innate immune response to pathogens. In particular, NLRP3 forms a multiprotein inflammasome complex responsible for the maturation of interleukin (IL)-1β. Our aim was to delineate the role of the NLRP3 inflammasome in macrophages, and the contribution of IL-1β to the host defense against Citrobacter rodentium acute infection in mice. Nlrp3−/− and background C57BL/6 (WT) mice were infected by orogastric gavage, received IL-1β (0.5 µg/mouse; ip) on 0, 2, and 4 days post-infection (DPI), and assessed on 6 and 10 DPI. Infected Nlrp3−/− mice developed severe colitis; IL-1β treatments reduced colonization, abrogated dissemination of bacteria to mesenteric lymph nodes, and protected epithelial integrity of infected Nlrp3−/− mice. In contrast, IL-1β treatments of WT mice had an opposite effect with increased penetration of bacteria and barrier disruption. Microscopy showed reduced damage in Nlrp3−/− mice, and increased severity of disease in WT mice with IL-1β treatments, in particular on 10 DPI. Secretion of some pro-inflammatory plasma cytokines was dissipated in Nlrp3−/− compared to WT mice. IL-1β treatments elevated macrophage infiltration into infected crypts in Nlrp3−/− mice, suggesting that IL-1β may improve macrophage function, as exogenous administration of IL-1β increased phagocytosis of C. rodentium by peritoneal Nlrp3−/− macrophages in vitro. As well, the exogenous administration of IL-1β to WT peritoneal macrophages damaged the epithelial barrier of C. rodentium-infected polarized CMT-93 cells. Treatment of Nlrp3−/− mice with IL-1β seems to confer protection against C. rodentium infection by reducing colonization, protecting epithelial integrity, and improving macrophage activity, while extraneous IL-1β appeared to be detrimental to WT mice. Together, these findings highlight the importance of balanced cytokine responses as IL-1β improved bacterial clearance in Nlrp3−/− mice but increased tissue damage when given to WT mice.

IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

“…Chung and colleagues demonstrated that IL1β signaling drives an early TH17 differentiation [47]. In addition it was shown that balanced IL1β activity is required for the host response to C. rodentium infection as IL1β improved the bacterial clearance but also increased tissue damage [48]. These results are in accordance with those of our study as we found that increased expression of IL17 and IL22 in the colon of C. rodentium -infected CD4-IL10ko mice was accompanied by elevated IL1β expression.…”

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). Unlike for S. typhimurium, NLRP3 and NLRC4 were shown to sense C. rodentium in nonhematopoietic cells, most likely in intestinal epithelial cells Nordlander et al 2013;Song-Zhao et al 2013).…”

Inflammasome Activation by ATP Enhances Citrobacter rodentium Clearance through ROS Generation

“…In our previous work, we showed that extraneous IL-1β improves the ability of macrophages to phagocytose C. rodentium in Nlrp3 -/- mice and that clearance of infection is dependent on the NLRP3 inflammasome [20]. As an extension of these findings, we aimed to optimize bacterial handling and hypothesized that increasing inflammasome activation would also improve the ability of macrophages to kill these pathogens.…”