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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.

Rac2-Deficiency Leads to Exacerbated and Protracted Colitis in Response to Citrobacter rodentium Infection