Modeling the Role of Peroxisome Proliferator-Activated Receptor c and MicroRNA-146 in Mucosal Immune Responses to Clostridium difficile

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dc.contributorVirginia Techen
dc.contributor.authorViladomiu, Monicaen
dc.contributor.authorHontecillas, Raquelen
dc.contributor.authorPedragosa, Mireiaen
dc.contributor.authorCarbo, Adriaen
dc.contributor.authorHoops, Stefanen
dc.contributor.authorMichalak, Pawelen
dc.contributor.authorMichalak, Katarzynaen
dc.contributor.authorGuerrant, Richard L.en
dc.contributor.authorRoche, James K.en
dc.contributor.authorWarren, Cirle A.en
dc.contributor.authorBassaganya-Riera, Josepen
dc.date.accessed2014-05-13en
dc.date.accessioned2014-06-17T20:12:08Zen
dc.date.available2014-06-17T20:12:08Zen
dc.date.issued2012-10-11en
dc.description.abstractClostridium difficile is an anaerobic bacterium that has re-emerged as a facultative pathogen and can cause nosocomial diarrhea, colitis or even death. Peroxisome proliferator-activated receptor (PPAR) c has been implicated in the prevention of inflammation in autoimmune and infectious diseases; however, its role in the immunoregulatory mechanisms modulating host responses to C. difficile and its toxins remains largely unknown. To characterize the role of PPARc in C. difficileassociated disease (CDAD), immunity and gut pathology, we used a mouse model of C. difficile infection in wild-type and T cell-specific PPARc null mice. The loss of PPARc in T cells increased disease activity and colonic inflammatory lesions following C. difficile infection. Colonic expression of IL-17 was upregulated and IL-10 downregulated in colons of T cellspecific PPARc null mice. Also, both the loss of PPARc in T cells and C. difficile infection favored Th17 responses in spleen and colonic lamina propria of mice with CDAD. MicroRNA (miRNA)-sequencing analysis and RT-PCR validation indicated that miR-146b was significantly overexpressed and nuclear receptor co-activator 4 (NCOA4) suppressed in colons of C. difficile infected mice. We next developed a computational model that predicts the upregulation of miR-146b, downregulation of the PPARc co-activator NCOA4, and PPARc, leading to upregulation of IL-17. Oral treatment of C. difficile-infected mice with the PPARc agonist pioglitazone ameliorated colitis and suppressed pro-inflammatory gene expression. In conclusion, our data indicates that miRNA-146b and PPARc activation may be implicated in the regulation of Th17 responses and colitis in C. difficile-infected mice.en
dc.description.sponsorshipSupported in part by National Institutes of Health 5R01AT004308 to JB-R, NIAID Contract No. HHSN272201000056C to JB-R and funds from the Nutritional Immunology and Molecular Medicine Laboratory. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.identifier.citationViladomiu M, Hontecillas R, Pedragosa M, Carbo A, Hoops S, et al. (2012) Modeling the Role of Peroxisome Proliferator-Activated Receptor γ and MicroRNA-146 in Mucosal Immune Responses to Clostridium difficile. PLoS ONE 7(10): e47525.en
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0047525en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://hdl.handle.net/10919/48999en
dc.identifier.urlhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0047525en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectClostridium difficilen
dc.subjectColonen
dc.subjectGene expressionen
dc.subjectGene targetingen
dc.subjectImmune responseen
dc.subjectLesionsen
dc.subjectMicroRNAen
dc.subjectT Cellsen
dc.titleModeling the Role of Peroxisome Proliferator-Activated Receptor c and MicroRNA-146 in Mucosal Immune Responses to Clostridium difficileen
dc.title.serialPLoS ONEen
dc.typeArticle - Refereeden

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