Differential TLR2 downstream signaling regulates lipid metabolism and cytokine production triggered by Mycobacterium bovis BCG infection

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• 作者：Patr铆cia E. Almeida ; Nat谩lia R. Roque ; Kelly G. Magalh茫es ; Katherine A. Mattos ; Livia Teixeira ; Clarissa Maya-Monteiro ; Cec铆lia J. Almeida ; Hugo C. Castro-Faria-Neto ; Bernhard Ryffel ; Val茅rie F.J. Quesniaux ; Patr铆cia T. Bozza
• 关键词：ADRP ; adipose differentiation related protein ; BCG ; Bacillus Calmette Gu&eacute ; rin ; IL ; interleukin ; NF-魏B ; nuclear factor-魏B ; M尾-CD ; methyl-尾-cyclodextrin ; PAMP ; pathogen-associated molecular patterns ; PGE2 ; prostaglandin E2 ; PPAR纬 ; peroxisome proliferator-activated receptor gamma ; TLR ; Toll-like receptor
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：January, 2014
• 年：2014
• 卷：1841
• 期：1
• 页码：97-107
• 全文大小：1131 K

文摘

The nuclear receptor PPAR纬 acts as a key modulator of lipid metabolism, inflammation and pathogenesis in BCG-infected macrophages. However, the molecular mechanisms involved in PPAR纬 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纬 expression, lipid body formation and cytokine synthesis in macrophages during BCG infection. BCG induces NF-魏B activation and increased PPAR纬 expression in a TLR2-dependent manner. Furthermore, BCG-triggered increase of lipid body biogenesis was inhibited by the PPAR纬 antagonist GW9662, but not by the NF-魏B inhibitor JSH-23. In contrast, KC/CXCL1 production was largely dependent on NF-魏B but not on PPAR纬. 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纬 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-伪 synthesis was not affected. Disruption of rafts recapitulates the latter result, inhibiting lipid body formation, but not TNF-伪 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纬-dependent and NF-魏B-independent pathways, leading to increased macrophage lipid accumulation and down-modulation of macrophage response.