Lactate promotes macrophage HMGB1 lactylation,acetylation, and exosomal release in polymicrobial sepsis |
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| Authors: | Kun Yang Min Fan Xiaohui Wang Jingjing Xu Yana Wang Fei Tu P. Spencer Gill Tuanzhu Ha Li Liu David L. Williams Chuanfu Li |
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| Affiliation: | 1.Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN USA ;2.Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN USA ;3.Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu China |
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| Abstract: | 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.Subject terms: Infectious diseases, Signal transduction, Epigenetics |
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