Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon.
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.
Peyrin-Biroulet
Laurent
L
Institut National de la Santé et de la Recherche Médicale, U795, F-59037 Lille, France.
Beisner
Julia
J
Wang
Guoxing
G
Nuding
Sabine
S
Oommen
Sajit Thottathil
ST
Kelly
Denise
D
Parmentier-Decrucq
Erika
E
Dessein
Rodrigue
R
Merour
Emilie
E
Chavatte
Philipe
P
Grandjean
Teddy
T
Bressenot
Aude
A
Desreumaux
Pierre
P
Colombel
Jean-Frédéric
JF
Desvergne
Béatrice
B
Stange
Eduard F
EF
Wehkamp
Jan
J
Chamaillard
Mathias
M
D000818:Animals; D001419:Bacteria / Q000276:immunology*; D002460:Cell Line; D003106:Colon / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000473:pathology; D005658:Fungi / Q000276:immunology*; D005786:Gene Expression Regulation; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D007082:Ileum / Q000276:immunology / Q000382:microbiology; D007113:Immunity, Innate / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D047495:PPAR gamma / Q000172:deficiency / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism
C406407:DEFB1 protein, human; D047495:PPAR gamma; D023083:beta-Defensins