Mycobacterium bovis bacillus Calmette-Guérin infection induces TLR2-dependent peroxisome proliferator-activated receptor γ expression and activation: Functions in inflammation, lipid metabolism, and pathogenesis

Patrícia E. Almeida, Adriana R. Silva, Clarissa M. Maya-Monteiro, Dániel Töröcsik, Heloisa D'Ávila, Balázs Dezsö, Kelly G. Magalhães, Hugo C. Castro-Faria-Neto, Laszlo Nagy, Patrícia T. Bozza

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97 Citations (Scopus)

Abstract

Macrophages have important roles in both lipid metabolism and inflammation and are central to immunity to intracellular pathogens. Foam-like, lipid-laden macrophages are present during the course of mycobacterial infection and have recently been implicated in mycobacterial pathogenesis. In this study, we analyzed the molecular mechanisms underlying the formation of macrophage lipid bodies (lipid droplets) during Mycobacterium bovis bacillus Calmette- Guérin (BCG) infection, focusing on the role of the lipid-activated nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). We found that BCG infection induced increased expression of PPARγ that paralleled the augmented lipid body formation and PGE 2 synthesis in mouse peritoneal macrophages. BCG-induced PPARγ expression and lipid body formation were diminished in macrophages from TLR2-deficient mice, suggesting a key role for TLR2. The function of PPARγ in modulating BCG infection was demonstrated by the capacity of the PPARγ agonist BRL49653 to potentiate lipid body formation and PGE2 production; furthermore, pretreatment with the PPARγ antagonist GW9662 inhibited BCG-induced lipid body formation and PGE2 production. BCG-induced MIP-1α, IL12p70, TNF-α, and IL6 production was not inhibited by GW9662 treatment. Nonpathogenic Mycobacterium smegmatis failed to induce PPARγ expression or lipid body formation. Moreover, inhibition of PPARγ by GW9662 enhanced the mycobacterial killing capacity of macrophages. Our findings show that PPARγ is involved in lipid body biogenesis, unravels a cross-talk between the innate immune receptor TLR2 and the lipid-activated nuclear receptor PPARγ that coordinates lipid metabolism and inflammation in BCG-infected macrophages, thereby potentially affecting mycobacterial pathogenesis.

Original languageEnglish
Pages (from-to)1337-1345
Number of pages9
JournalJournal of Immunology
Volume183
Issue number2
DOIs
Publication statusPublished - Jul 15 2009

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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