Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202;
J Immunol. 2014 Mar 1;192(5):2357-65. doi: 10.4049/jimmunol.1302375. Epub 2014 Jan 31.
Polymicrobial sepsis induces organ failure and is accompanied by overwhelming inflammatory response and impairment of microbial killing. Peroxisome proliferator-activated receptor (PPAR)-γ is a nuclear receptor with pleiotropic effects on lipid metabolism, inflammation, and cell proliferation. The insulin-sensitizing drugs thiazolidinediones (TZDs) are specific PPAR-γ agonists. TZDs exert anti-inflammatory actions in different disease models, including polymicrobial sepsis. The TZD pioglitazone, which has been approved by the U.S. Food and Drug Administration, improves sepsis outcome; however, the molecular programs that mediate its effect have not been determined. In a murine model of sepsis, we now show that pioglitazone treatment improves microbial clearance and enhances neutrophil recruitment to the site of infection. We also observed reduced proinflammatory cytokine production and high IL-10 levels in pioglitazone-treated mice. These effects were associated with a decrease in STAT-1-dependent expression of MyD88 in vivo and in vitro. IL-10R blockage abolished PPAR-γ-mediated inhibition of MyD88 expression. These data demonstrate that the primary mechanism by which pioglitazone protects against polymicrobial sepsis is through the impairment of MyD88 responses. This appears to represent a novel regulatory program. In this regard, pioglitazone provides advantages as a therapeutic tool, because it improves different aspects of host defense during sepsis, ultimately enhancing survival.
多微生物脓毒症会导致器官衰竭，并伴有压倒性的炎症反应和微生物杀伤能力受损。过氧化物酶体增殖物激活受体 (PPAR)-γ 是一种具有多种作用的核受体，可影响脂质代谢、炎症和细胞增殖。胰岛素增敏药物噻唑烷二酮类 (TZDs) 是特定的 PPAR-γ 激动剂。TZDs 在包括多微生物脓毒症在内的不同疾病模型中具有抗炎作用。噻唑烷二酮吡格列酮已被美国食品和药物管理局批准用于改善脓毒症的预后；然而，介导其作用的分子程序尚未确定。在脓毒症的小鼠模型中，我们现在表明吡格列酮治疗可改善微生物清除率，并增强中性粒细胞向感染部位的募集。我们还观察到，在吡格列酮治疗的小鼠中，促炎细胞因子的产生减少，IL-10 水平升高。这些效应与体内和体外 STAT-1 依赖性 MyD88 表达减少有关。IL-10R 阻断消除了 PPAR-γ 对 MyD88 表达的抑制作用。这些数据表明，吡格列酮预防多微生物脓毒症的主要机制是通过损害 MyD88 反应。这似乎代表了一种新的调控程序。在这方面，吡格列酮作为一种治疗工具具有优势，因为它在脓毒症期间改善了宿主防御的不同方面，最终提高了生存率。
