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

Ramzi Fattouh, Cong Hui Guo, Grace Y. Lam, Melanie Gareau, Bo Yee Ngan, Michael Glogauer, Aleixo M. Muise, John H. Brumell

Research output: Contribution to journalArticle

13 Scopus citations

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.

Original languageEnglish (US)
Article numbere61629
JournalPLoS One
Volume8
Issue number4
DOIs
StatePublished - Apr 16 2013
Externally publishedYes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Fattouh, R., Guo, C. H., Lam, G. Y., Gareau, M., Ngan, B. Y., Glogauer, M., Muise, A. M., & Brumell, J. H. (2013). Rac2-Deficiency Leads to Exacerbated and Protracted Colitis in Response to Citrobacter rodentium Infection. PLoS One, 8(4), [e61629]. https://doi.org/10.1371/journal.pone.0061629