| First Author | Almeida PE | Year | 2014 |
| Journal | Biochim Biophys Acta | Volume | 1841 |
| Issue | 1 | Pages | 97-107 |
| PubMed ID | 24120921 | Mgi Jnum | J:210048 |
| Mgi Id | MGI:5569442 | Doi | 10.1016/j.bbalip.2013.10.008 |
| Citation | Almeida PE, et al. (2014) Differential TLR2 downstream signaling regulates lipid metabolism and cytokine production triggered by Mycobacterium bovis BCG infection. Biochim Biophys Acta 1841(1):97-107 |
| abstractText | The nuclear receptor PPARgamma acts as a key modulator of lipid metabolism, inflammation and pathogenesis in BCG-infected macrophages. However, the molecular mechanisms involved in PPARgamma 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 PPARgamma expression, lipid body formation and cytokine synthesis in macrophages during BCG infection. BCG induces NF-kappaB activation and increased PPARgamma expression in a TLR2-dependent manner. Furthermore, BCG-triggered increase of lipid body biogenesis was inhibited by the PPARgamma antagonist GW9662, but not by the NF-kappaB inhibitor JSH-23. In contrast, KC/CXCL1 production was largely dependent on NF-kappaB but not on PPARgamma. 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 PPARgamma 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 PPARgamma-dependent and NF-kappaB-independent pathways, leading to increased macrophage lipid accumulation and down-modulation of macrophage response. |
