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.
Highlights
Sepsis is a life-threatening disease that is characterized by organ dysfunction and dysregulated host innate and inflammatory responses to the infection [1]
The present study demonstrated a novel role of lactate in promoting high mobility group box-1 (HMGB1) lactylation/acetylation and release via exosome secretion in macrophages
As an important damageassociated molecular pattern (DAMP) molecule, circulating HMGB1 plays a critical role in progression and late mortality of sepsis [10, 21]
Summary
Sepsis is a life-threatening disease that is characterized by organ dysfunction and dysregulated host innate and inflammatory responses to the infection [1]. Clinical evidence has revealed that the levels of circulating HMGB1 are markedly elevated and positively correlated with sepsis severity and mortality [7,8,9]. Zhang et al reported a novel function of glycolysis-derived lactate in macrophages whereby it is utilized in modulating nuclear histones through the addition of lactyl groups to the lysine (K) residues of histones [14]. This process is termed as “lactylation.”’ it remains unknown whether lactate could promote HMGB1 lactylation and release. Pharmacological inhibition of lactate production and/or lactate receptor GPR81-mediated signaling decreases circulating exosomal HMGB1 levels, which highlights lactate/lactate-associated signaling as a promising drug target in sepsis
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