Differential TLR2 downstream signaling regulates lipid metabolism and cytokine production triggered by Mycobacterium bovis BCG infection
Differential TLR2 downstream signaling regulates lipid metabolism and cytokine production triggered by Mycobacterium bovis BCG infection
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DOI：
10.1016/j.bbalip.2013.10.008
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发表时间：
2014-01-01
影响因子：
4.8
通讯作者：
Bozza, Patricia T.
中科院分区：
文献类型：
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作者：
Almeida, Patricia E.;Roque, Natalia R.;Bozza, Patricia T.
核受体PPAR γ在BCG感染的巨噬细胞中作为脂质代谢、炎症和发病机制的关键调节剂。然而，在感染过程中参与PPARgamma表达和功能的分子机制尚未完全了解。在这里，我们调查TLR 2触发的信号通路，参与的辅助受体和脂筏的机制，在BCG感染过程中的巨噬细胞的PPAR γ表达，脂质体的形成和细胞因子的合成。BCG以TLR 2依赖性方式诱导NF-κ B活化和增加PPAR γ表达。此外，BCG触发的脂质体生物合成的增加被PPAR γ拮抗剂GW 9662抑制，但不被NF-κ B抑制剂JSH-23抑制。相比之下，KC/CXCL 1的产生主要依赖于NF-κ B，而不是PPAR γ。BCG感染诱导巨噬细胞CD 36表达增加。此外，在BCG感染的巨噬细胞中，CD 36与TLR 2共免疫沉淀，表明其在BCG信号传导中与TLR 2相互作用。用CD 36中和抗体预处理显著抑制BCG诱导的PPAR γ表达、脂质体形成和PGE 2产生。在CD 36缺陷型巨噬细胞中BCG诱导的脂质体形成减少进一步证实了CD 36参与脂质体形成。类似地，CD 14和CD 11b/CD 18阻断也抑制BCG诱导的脂质体形成，而TNF-α合成不受影响。筏的破坏概括了后者的结果，抑制脂质体的形成，但不是BCG感染的巨噬细胞中TNF-α的合成。总之，我们的研究结果表明，CD 36-TLR 2合作和信号区室化筏内，转移宿主反应信号通过PPAR γ依赖性和NF-κ B非依赖性途径，导致增加巨噬细胞脂质积累和下调巨噬细胞反应。(C)2013爱思唯尔有限公司版权所有。
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.