Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1841, Issue 1, Pages 97-107Publisher
ELSEVIER
DOI: 10.1016/j.bbalip.2013.10.008
Keywords
Nuclear receptor; TLR; Lipid droplet; CD36; PPARgamma
Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq/Brazil)
- PAPES-FIOCRUZ
- PRONEX (MCT, Brazil)
- Fundacao de Amparo Pesquisa do Estado do Rio de Janeiro (FAPERJ, Brazil)
- French National Center for Scientific Research (CNRS)
- CNRS/FIOCRUZ [24201]
- Guggenheim Foundation
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The nuclear receptor PPAR gamma acts as a key modulator of lipid metabolism, inflammation and pathogenesis in BCG-infected macrophages. However, the molecular mechanisms involved in PPAR gamma expression and functions during infection are not completely understood. Here, we investigate signaling pathways triggered by TLR2, the involvement of co-receptors and lipid rafts in the mechanism of PPAR gamma expression, lipid body formation and cytokine synthesis in macrophages during BCG infection. BCG induces NF-kappa B activation and increased PPAR gamma expression in a TLR2-dependent manner. Furthermore, BCG-triggered increase of lipid body biogenesis was inhibited by the PPAR gamma antagonist GW9662, but not by the NF-kappa B inhibitor JSH-23. In contrast, KC/CXCL1 production was largely dependent on NF-KB but not on PPAR gamma. BCG infection induced increased expression of CD36 in macrophages in vitro. Moreover, CD36 co-immunoprecipitates with TLR2 in BCG-infected macrophages, suggesting its interaction with TLR2 in BCG signaling. Pretreatment with CD36 neutralizing antibodies significantly inhibited PPAR gamma expression, lipid body formation and PGE2 production induced by BCG. Involvement of CD36 in lipid body formation was further confirmed by decreased BCG-induced lipid body formation in CD36 deficient macrophages. Similarly, CD14 and CD11b/CD18 blockage also inhibited BCG-induced lipid body formation, whereas TNF-alpha synthesis was not affected. Disruption of rafts recapitulates the latter result, inhibiting lipid body formation, but not TNF-alpha synthesis in BCG-infected macrophages. In conclusion, our results suggest that CD36-TLR2 cooperation and signaling compartmentalization within rafts, divert host response signaling through PPAR gamma-dependent and NF-kappa B-independent pathways, leading to increased macrophage lipid accumulation and down-modulation of macrophage response. (C) 2013 Elsevier B.V. All rights reserved.
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