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.

高循环水平的乳酸和高迁移率组框 1 (HMGB1) 与脓毒症的严重程度和死亡率相关。然而，尚不清楚乳酸是否可以促进脓毒症期​​间 HMGB1 的释放。本研究证明了乳酸在多微生物脓毒症期间巨噬细胞 HMGB1 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，从而通过 p300/CBP 依赖性机制促进 HMGB1 的乳酸化。我们还观察到乳酸通过 Hippo/YAP 介导的去乙酰化酶 SIRT1 的抑制和 β-arrestin2 介导的乙酰化酶 p300/CBP 通过 G 蛋白偶联受体 81 (GPR81) 募集到细胞核来刺激 HMGB1 乙酰化。乳酸化/乙酰化 HMGB1 通过增加内皮通透性的外泌体分泌从巨噬细胞中释放出来。在体内减少乳酸产生和/或抑制 GPR81 介导的信号传导会降低循环外泌体 HMGB1 水平并改善多微生物败血症的存活结果。我们的研究结果为靶向乳酸/乳酸相关信号以对抗败血症提供了基础。