PPAR-γ/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis.
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.
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202;
Ana Elisa
AE
Ferreira
Flavia
F
Sisti
Fabiane
F
Sônego
Suojuan
S
Wang
Luciano Ribeiro
LR
Filgueiras
Stephanie
S
Brandt
Ana Paula Moreira
AP
Serezani
Hong
H
Du
Fernando Q
FQ
Cunha
Jose Carlos
JC
Alves-Filho
Carlos Henrique
CH
Serezani
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000276:immunology*; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000276:immunology*; D053701:Receptors, Interleukin-10 / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000276:immunology; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D045162:Thiazolidinediones / Q000494:pharmacology
D007004:Hypoglycemic Agents; C556062:IL10 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D047495:PPAR gamma; D053701:Receptors, Interleukin-10; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D045162:Thiazolidinediones; D016753:Interleukin-10; C089946:2,4-thiazolidinedione