IL-17 mediated the anti-microbial actions of PPAR gamma blockade during EAEC infection

Philipson, C., R. Hontecillas, and J. Bassaganya-Riera (2013) IL-17 mediated the anti-microbial actions of PPAR gamma blockade during EAEC infection, American Association of Immunologists Annual Meeting, Honolulu HI

Enteroaggregative Escherichia coli (EAEC) is an etiologic agent of enterocolitis and persistent diarrhea worldwide, especially in malnourished children and immunosuppressed individuals. Expression of IL-17, which is produced by a number of immune and epithelial cells, increases during EAEC infection. We previously demonstrated that blocking peroxisome proliferator-activated receptor gamma (PPARγ) enhances mucosal Th17 responses that contribute to bacterial clearance in EAEC-infected mice. Here we investigate whether IL-17 mediates the effects of PPARγ blockade in the gut. We show that increasing doses of PPARg antagonist GW9662 (0.5, 1, or 2µM) directly correlated to increased IL-17 expression in the colon. C57BL/6 wild type mice were challenged with EAEC strain JM221 on day 0 and administered anti IL-17 neutralizing antibody (50μg) i.p. on days 0, 2, and 4 of the study. Anti-IL17 antibody-mediated neutralization of IL-17 abrogated the beneficial effects of PPARγ blockade on weight loss and fecal EAEC burden. In addition, infiltration of CD11c+ dendritic cells and CD4+ T cells into the colonic lamina propria, as well as colonic antimicrobial peptide expression were significantly reduced in mice treated with αIL-17 and GW9662 when compared to mice receiving GW9662 alone. These findings suggest that the beneficial effects from PPARγ blockade in disease activity and bacterial burden during EAEC infection are largely mediated through an IL-17-dependent mechanism.