Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling.
Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling.
复制标题
乳酸盐通过GPR81介导的信号转导抑制雅普和NF-κ B活化抑制巨噬细胞对LPS刺激的促炎反应
DOI：
10.3389/fimmu.2020.587913
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发表时间：
2020
影响因子：
7.3
通讯作者：
Li C
中科院分区：
文献类型：
--
作者：
Yang K;Xu J;Fan M;Tu F;Wang X;Ha T;Williams DL;Li C
癌症研究的最新证据表明，乳酸对癌症的先天免疫反应具有抑制作用。这项研究调查了乳酸抑制巨噬细胞促炎症反应的机制。在存在或不存在乳酸的情况下用 LPS 处理巨噬细胞 [Raw 264.7 和骨髓来源的巨噬细胞 (BMDM)]。检查促炎细胞因子、NF-κB 和 YAP 激活以及核转位。我们的结果表明，乳酸显着减弱 LPS 刺激的巨噬细胞 TNF-α 和 IL-6 的产生。乳酸还抑制 LPS 刺激的巨噬细胞 NF-κB 和 YAP 活化以及巨噬细胞中的核转位。有趣的是，YAP 激活和核转位是 LPS 刺激巨噬细胞 NF-κB 激活和 TNFα 产生所必需的。重要的是，乳酸抑制 YAP 激活和核转位是由 GPR81 依赖性 AMKP 和 LATS 激活介导的，后者磷酸化 YAP，导致 YAP 失活。最后，我们证明LPS刺激诱导YAP和NF-κB亚基p65之间的相互作用，而乳酸降低YAP和NF-κB的相互作用，从而抑制LPS诱导的促炎细胞因子的产生。我们的研究表明，乳酸通过 GPR81 介导的 YAP 失活，在抑制巨噬细胞促炎细胞因子产生方面发挥了以前未知的作用，从而破坏了 YAP 和 NF-κB 相互作用以及巨噬细胞中的核转位。
Recent evidence from cancer research indicates that lactate exerts a suppressive effect on innate immune responses in cancer. This study investigated the mechanisms by which lactate suppresses macrophage pro-inflammatory responses. Macrophages [Raw 264.7 and bone marrow derived macrophages (BMDMs)] were treated with LPS in the presence or absence of lactate. Pro-inflammatory cytokines, NF-κB and YAP activation and nuclear translocation were examined. Our results show that lactate significantly attenuates LPS stimulated macrophage TNF-α and IL-6 production. Lactate also suppresses LPS stimulated macrophage NF-κB and YAP activation and nuclear translocation in macrophages. Interestingly, YAP activation and nuclear translocation are required for LPS stimulated macrophage NF-κB activation and TNFα production. Importantly, lactate suppressed YAP activation and nuclear translocation is mediated by GPR81 dependent AMKP and LATS activation which phosphorylates YAP, resulting in YAP inactivation. Finally, we demonstrated that LPS stimulation induces an interaction between YAP and NF-κB subunit p65, while lactate decreases the interaction of YAP and NF-κB, thus suppressing LPS induced pro-inflammatory cytokine production. Our study demonstrates that lactate exerts a previously unknown role in the suppression of macrophage pro-inflammatory cytokine production via GPR81 mediated YAP inactivation, resulting in disruption of YAP and NF-κB interaction and nuclear translocation in macrophages.