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

• DOI: 10.1371/journal.pone.0061629
• Publication Date: 2013-04-16T21:04:53Z
• Authors: Ramzi Fattouh; Cong-Hui Guo; Grace Y. Lam; Melanie G. Gareau; Bo-Yee Ngan; Michael Glogauer; Aleixo M. Muise; John H. Brumell
• Keywords: Male; 0301 basic medicine; General Science & Technology; Colon; Knockout; Science; Immunology; 610; Crohn's Disease; Autoimmune Disease; Mice; 03 medical and health sciences; 2.1 Biological and endogenous factors; Animals; Aetiology; Mice, Knockout; Biomedical and Clinical Sciences; RAC2 GTP-Binding Protein; Inflammatory Bowel Disease; Q; R; Enterobacteriaceae Infections; Colitis; rac GTP-Binding Proteins; 3. Good health; Medicine; Citrobacter rodentium; Digestive Diseases; Research Article

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.