Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon
Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon
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DOI：
10.1073/pnas.0905745107
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发表时间：
2010-05-11
影响因子：
11.1
通讯作者：
Chamaillard, Mathias
中科院分区：
文献类型：
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作者：
Peyrin-Biroulet, Laurent;Beisner, Julia;Chamaillard, Mathias
克罗恩病（CD）是人类炎症性肠病的主要形式，其特征在于原发性免疫缺陷。核受体过氧化物酶体增殖物激活受体γ（PPARgamma）是肠道内稳态响应饮食和微生物来源的信号所必需的。然而，它在宿主防御中的作用仍然未知。我们展示了这个PPAR。作为一种抗微生物因子，通过维持结肠中β-防御素亚群的组成性上皮表达发挥作用，所述亚群包括小鼠中的mDefB 10和人类中的DEFB 1。Ppar γ突变动物的结肠粘膜显示出对肠道微生物群的几种主要组分的有缺陷的杀伤，包括白色念珠菌、脆弱拟杆菌、粪肠球菌和大肠杆菌。使用抗mDefB 10阻断抗体中和杀大肠杆菌活性以PPAR γ依赖性方式有效。DEFB 1表达所需的功能性启动子变体对克罗恩氏结肠炎和回肠结肠炎具有很强的保护作用（比值比，0.559; P = 0.018）。因此，CD中的结肠受累与DEFB 1表达减少特异性相关，而与炎症无关。这些发现支持开发以PPAR γ为靶点的治疗和/或营养方法，通过恢复CD中的抗微生物免疫来预防结肠炎症。
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(PPAR gamma) 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 PPAR. 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 Ppar gamma 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 PPAR gamma-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 PPAR gamma-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.