Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis.
Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis.
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乳酸促进巨噬细胞HMGB1乳糖，乙酰化和外座子体释放中的多因素败血症。
DOI：
10.1038/s41418-021-00841-9
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发表时间：
2022-01
影响因子：
12.4
通讯作者：
Li C
中科院分区：
文献类型：
--
作者：
Yang K;Fan M;Wang X;Xu J;Wang Y;Tu F;Gill PS;Ha T;Liu L;Williams DL;Li C
高循环水平的乳酸和高迁移率族蛋白1（HMGB 1）与脓毒症的严重程度和死亡率相关。然而，目前尚不清楚乳酸是否可以促进脓毒症期间HMGB 1的释放。本研究证实了乳酸在多菌性脓毒症中巨噬细胞HMGB 1乳酸化和乙酰化中的新作用。我们发现，巨噬细胞可以通过单羧酸转运蛋白（MCT）摄取细胞外乳酸，通过p300/CBP依赖性机制促进HMGB 1的乳酸化。我们还观察到乳酸通过Hippo/YAP介导的去乙酰化酶SIRT 1的抑制和β-arrestin 2介导的乙酰化酶p300/CBP通过G蛋白偶联受体81（GPR 81）向细胞核的募集来刺激HMGB 1乙酰化。乳酸化/乙酰化HMGB 1通过外泌体分泌从巨噬细胞释放，外泌体分泌增加内皮通透性。在体内减少乳酸产生和/或抑制GPR 81介导的信号传导可降低循环外泌体HMGB 1水平并改善多微生物败血症的生存结局。我们的研究结果为靶向乳酸/乳酸相关信号转导以对抗脓毒症提供了基础。
High circulating levels of lactate and high mobility group box-1 (HMGB1) are associated with the severity and mortality of sepsis. However, it is unclear whether lactate could promote HMGB1 release during sepsis. The present study demonstrated a novel role of lactate in HMGB1 lactylation and acetylation in macrophages during polymicrobial sepsis. We found that macrophages can uptake extracellular lactate via monocarboxylate transporters (MCTs) to promote HMGB1 lactylation via a p300/CBP-dependent mechanism. We also observed that lactate stimulates HMGB1 acetylation by Hippo/YAP-mediated suppression of deacetylase SIRT1 and β-arrestin2-mediated recruitment of acetylases p300/CBP to the nucleus via G protein-coupled receptor 81 (GPR81). The lactylated/acetylated HMGB1 is released from macrophages via exosome secretion which increases endothelium permeability. In vivo reduction of lactate production and/or inhibition of GPR81-mediated signaling decreases circulating exosomal HMGB1 levels and improves survival outcome in polymicrobial sepsis. Our results provide the basis for targeting lactate/lactate-associated signaling to combat sepsis.
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