PPAR-g/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis

Ana Elisa Ferreira, Flavia Sisti, Fabiane Sônego, Suojuan Wang, Luciano Ribeiro Filgueiras, Stephanie Brandt, Ana Paula Moreira Serezani, Hong Du, Fernando Q. Cunha, Jose Carlos Alves-Filho, Carlos Henrique Serezani

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Polymicrobial sepsis induces organ failure and is accompanied by overwhelming inflammatory response and impairment of microbial killing. Peroxisome proliferator-Activated receptor (PPAR)-g is a nuclear receptor with pleiotropic effects on lipid metabolism, inflammation, and cell proliferation. The insulin-sensitizing drugs thiazolidinediones (TZDs) are specific PPAR-g 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-g-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.

Original languageEnglish (US)
Pages (from-to)2357-2365
Number of pages9
JournalJournal of Immunology
Volume192
Issue number5
DOIs
StatePublished - Mar 1 2014

Fingerprint

pioglitazone
Peroxisome Proliferator-Activated Receptors
Interleukin-10
Sepsis
Thiazolidinediones
Neutrophil Infiltration
United States Food and Drug Administration
Cytoplasmic and Nuclear Receptors
Lipid Metabolism
Anti-Inflammatory Agents
Cell Proliferation
Insulin
Cytokines
Inflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Ferreira, A. E., Sisti, F., Sônego, F., Wang, S., Filgueiras, L. R., Brandt, S., ... Serezani, C. H. (2014). PPAR-g/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis. Journal of Immunology, 192(5), 2357-2365. https://doi.org/10.4049/jimmunol.1302375

PPAR-g/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis. / Ferreira, Ana Elisa; Sisti, Flavia; Sônego, Fabiane; Wang, Suojuan; Filgueiras, Luciano Ribeiro; Brandt, Stephanie; Serezani, Ana Paula Moreira; Du, Hong; Cunha, Fernando Q.; Alves-Filho, Jose Carlos; Serezani, Carlos Henrique.

In: Journal of Immunology, Vol. 192, No. 5, 01.03.2014, p. 2357-2365.

Research output: Contribution to journalArticle

Ferreira, AE, Sisti, F, Sônego, F, Wang, S, Filgueiras, LR, Brandt, S, Serezani, APM, Du, H, Cunha, FQ, Alves-Filho, JC & Serezani, CH 2014, 'PPAR-g/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis', Journal of Immunology, vol. 192, no. 5, pp. 2357-2365. https://doi.org/10.4049/jimmunol.1302375
Ferreira AE, Sisti F, Sônego F, Wang S, Filgueiras LR, Brandt S et al. PPAR-g/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis. Journal of Immunology. 2014 Mar 1;192(5):2357-2365. https://doi.org/10.4049/jimmunol.1302375
Ferreira, Ana Elisa ; Sisti, Flavia ; Sônego, Fabiane ; Wang, Suojuan ; Filgueiras, Luciano Ribeiro ; Brandt, Stephanie ; Serezani, Ana Paula Moreira ; Du, Hong ; Cunha, Fernando Q. ; Alves-Filho, Jose Carlos ; Serezani, Carlos Henrique. / PPAR-g/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis. In: Journal of Immunology. 2014 ; Vol. 192, No. 5. pp. 2357-2365.
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