Modeling the role of peroxisome proliferator-activated receptor ? and microRNA-146 in mucosal immune responses to Clostridium difficile.

ABSTRACT: Clostridium 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) ? 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 PPAR? in C. difficile-associated disease (CDAD), immunity and gut pathology, we used a mouse model of C. difficile infection in wild-type and T cell-specific PPAR? null mice. The loss of PPAR? 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 cell-specific PPAR? null mice. Also, both the loss of PPAR? 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 PPAR? co-activator NCOA4, and PPAR?, leading to upregulation of IL-17. Oral treatment of C. difficile-infected mice with the PPAR? agonist pioglitazone ameliorated colitis and suppressed pro-inflammatory gene expression. In conclusion, our data indicates that miRNA-146b and PPAR? activation may be implicated in the regulation of Th17 responses and colitis in C. difficile-infected mice.

SUBMITTER: Viladomiu M 

PROVIDER: S-EPMC3469550 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature