TY - JOUR
T1 - Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon
AU - Peyrin-Biroulet, Laurent
AU - Beisner, Julia
AU - Wang, Guoxing
AU - Nuding, Sabine
AU - Oommen, Sajit Thottathil
AU - Kelly, Denise
AU - Parmentier-Decrucq, Erika
AU - Dessein, Rodrigue
AU - Merour, Emilie
AU - Chavatte, Philipe
AU - Grandjean, Teddy
AU - Bressenot, Aude
AU - Desreumaux, Pierre
AU - Colombel, Jean-Frédéric
AU - Desvergne, Béatrice
AU - Stange, Eduard F
AU - Wehkamp, Jan
AU - Chamaillard, Mathias
PY - 2010/5/11
Y1 - 2010/5/11
N2 - Crohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for intestinal homeostasis in response to both dietary- and microbiota-derived signals. Its role in host defense remains unknown, however. We show that PPARgamma functions as an antimicrobial factor by maintaining constitutive epithelial expression of a subset of beta-defensin in the colon, which includes mDefB10 in mice and DEFB1 in humans. Colonic mucosa of Ppargamma mutant animals shows defective killing of several major components of the intestinal microbiota, including Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli. Neutralization of the colicidal activity using an anti-mDefB10 blocking antibody was effective in a PPARgamma-dependent manner. A functional promoter variant that is required for DEFB1 expression confers strong protection against Crohn's colitis and ileocolitis (odds ratio, 0.559; P = 0.018). Consistently, colonic involvement in CD is specifically linked to reduced expression of DEFB1 independent of inflammation. These findings support the development of PPARgamma-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.
AB - Crohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for intestinal homeostasis in response to both dietary- and microbiota-derived signals. Its role in host defense remains unknown, however. We show that PPARgamma functions as an antimicrobial factor by maintaining constitutive epithelial expression of a subset of beta-defensin in the colon, which includes mDefB10 in mice and DEFB1 in humans. Colonic mucosa of Ppargamma mutant animals shows defective killing of several major components of the intestinal microbiota, including Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli. Neutralization of the colicidal activity using an anti-mDefB10 blocking antibody was effective in a PPARgamma-dependent manner. A functional promoter variant that is required for DEFB1 expression confers strong protection against Crohn's colitis and ileocolitis (odds ratio, 0.559; P = 0.018). Consistently, colonic involvement in CD is specifically linked to reduced expression of DEFB1 independent of inflammation. These findings support the development of PPARgamma-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.
KW - beta-defensin 1
KW - Crohn's disease
KW - microbiota
KW - nutrition
KW - PPAR-gamma
U2 - 10.1073/pnas.0905745107
DO - 10.1073/pnas.0905745107
M3 - Article
C2 - 20421464
SN - 0027-8424
VL - 107
SP - 8772
EP - 8777
JO - PNAS
JF - PNAS
IS - 19
ER -