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Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection.

ABSTRACT: Recent genetic-based studies have implicated a number of immune-related genes in the pathogenesis of inflammatory bowel disease (IBD). Our recent genetic studies showed that RAC2 is associated with human IBD; however, its role in disease pathogenesis is unclear. Given Rac2's importance in various fundamental immune cell processes, we investigated whether a defect in Rac2 may impair host immune responses in the intestine and promote disease in the context of an infection-based (Citrobacter rodentium) model of colitis. In response to infection, Rac2(-/-) mice showed i) worsened clinical symptoms (days 13-18), ii) increased crypt hyperplasia at days 11 and 22 (a time when crypt hyperplasia was largely resolved in wild-type mice; WT), and iii) marked mononuclear cell infiltration characterized by higher numbers of T (CD3(+)) cells (day 22), compared to WT-infected mice. Moreover, splenocytes harvested from infected Rac2(-/-) mice and stimulated in vitro with C. rodentium lysate produced considerably higher levels of interferon-γ and interleukin-17A. The augmented responses observed in Rac2(-/-) mice did not appear to stem from Rac2's role in NADPH oxidase-driven reactive oxygen species production as no differences in crypt hyperplasia, nor inflammation, were observed in infected NOX2(-/-) mice compared to WT. Collectively, our findings demonstrate that Rac2(-/-) mice develop more severe disease when subjected to a C. rodentium-induced model of infectious colitis, and suggest that impaired Rac2 function may promote the development of IBD in humans.

SUBMITTER: Fattouh R

PROVIDER: S-EPMC3628927 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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)-1?. Our aim was to delineate the role of the NLRP3 inflammasome in macrophages, and the contribution of IL-1? 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-1? (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-1? treatments reduced colonization, abrogated dissemination of bacteria to mesenteric lymph nodes, and protected epithelial integrity of infected Nlrp3(-/-) mice. In contrast, IL-1? 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-1? treatments, in particular on 10 DPI. Secretion of some pro-inflammatory plasma cytokines was dissipated in Nlrp3(-/-) compared to WT mice. IL-1? treatments elevated macrophage infiltration into infected crypts in Nlrp3(-/-) mice, suggesting that IL-1? may improve macrophage function, as exogenous administration of IL-1? increased phagocytosis of C. rodentium by peritoneal Nlrp3(-/-) macrophages in vitro. As well, the exogenous administration of IL-1? to WT peritoneal macrophages damaged the epithelial barrier of C. rodentium-infected polarized CMT-93 cells. Treatment of Nlrp3(-/-) mice with IL-1? seems to confer protection against C. rodentium infection by reducing colonization, protecting epithelial integrity, and improving macrophage activity, while extraneous IL-1? appeared to be detrimental to WT mice. Together, these findings highlight the importance of balanced cytokine responses as IL-1? improved bacterial clearance in Nlrp3(-/-) mice but increased tissue damage when given to WT mice.

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Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection.

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