Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection.
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 vario...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3628927?pdf=render |
| _version_ | 1819102887363477504 |
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| author | Ramzi Fattouh Cong-Hui Guo Grace Y Lam Melanie G Gareau Bo-Yee Ngan Michael Glogauer Aleixo M Muise John H Brumell |
| author_facet | Ramzi Fattouh Cong-Hui Guo Grace Y Lam Melanie G Gareau Bo-Yee Ngan Michael Glogauer Aleixo M Muise John H Brumell |
| author_sort | Ramzi Fattouh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T01:41:42Z |
| format | Article |
| id | doaj.art-257e832d2d974e3eba67135d104855d0 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T01:41:42Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-257e832d2d974e3eba67135d104855d02022-12-21T18:43:12ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0184e6162910.1371/journal.pone.0061629Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection.Ramzi FattouhCong-Hui GuoGrace Y LamMelanie G GareauBo-Yee NganMichael GlogauerAleixo M MuiseJohn H BrumellRecent 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.http://europepmc.org/articles/PMC3628927?pdf=render |
| spellingShingle | Ramzi Fattouh Cong-Hui Guo Grace Y Lam Melanie G Gareau Bo-Yee Ngan Michael Glogauer Aleixo M Muise John H Brumell Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection. PLoS ONE |
| title | Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection. |
| title_full | Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection. |
| title_fullStr | Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection. |
| title_full_unstemmed | Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection. |
| title_short | Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection. |
| title_sort | rac2 deficiency leads to exacerbated and protracted colitis in response to citrobacter rodentium infection |
| url | http://europepmc.org/articles/PMC3628927?pdf=render |
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