title: 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.
authors.affiliation: Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Ramzi
authors.initials: R
authors.lastname: Fattouh
authors.forename: Cong-Hui
authors.initials: CH
authors.lastname: Guo
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Lam
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Gareau
authors.forename: Bo-Yee
authors.initials: BY
authors.lastname: Ngan
authors.forename: Michael
authors.initials: M
authors.lastname: Glogauer
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
authors.forename: John H
authors.initials: JH
authors.lastname: Brumell
mesh_terms: D000818:Animals; D044082:Citrobacter rodentium / Q000472:pathogenicity*; D003092:Colitis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000382:microbiology; D004756:Enterobacteriaceae Infections / Q000150:complications*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020744:rac GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D000097766:RAC2 GTP-Binding Protein
chemical_list: D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein