Lactate-induced macrophage HMGB1 lactylation promotes neutrophil extracellular trap formation in sepsis-associated acute kidney injury
Siwei Wei, Zijuan Dai, Lei Wu, Zhen Xiang, Xiaoxiao Yang, Liubing Jiang, Zhen Du
Abstract
Neutrophils play a key role in sepsis-associated acute kidney injury (SAKI), a common and life-threatening complication of organ failure. High mobility group box 1 (HMGB1) modulates inflammatory responses and the formation of neutrophil extracellular traps (NETs). The present work aimed to explore whether HMGB1 lactylation promotes NET formation and exacerbates SAKI. Venous blood samples were collected from healthy volunteers and SAKI patients. A SAKI mouse model was established using the cecal ligation and puncture method. A coculture system of macrophage-derived exosomes and neutrophils was established. Macrophage-derived exosomes were isolated and identified. ELISAs, immunofluorescence staining, coimmunoprecipitation, and Western blotting were utilized to determine protein levels. Elevated blood lactate levels were associated with increased HMGB1 levels in patients with SAKI. In mouse models, lactate increased HMGB1 expression, promoted NET formation, and exacerbated SAKI. Lactate stimulated M1 macrophages to secrete exosomes, leading to the accumulation and release of HMGB1 in the cytoplasm. Additionally, lactate promoted HMGB1 lactylation in macrophages, triggering the release of mitochondrial DNA from neutrophils and activating the cyclic GMP‒AMP synthase/stimulator of interferon genes pathway. This study revealed that lactate-induced HMGB1 lactylation in macrophages plays a role in promoting NET formation in SAKI through the cGAS/STING pathway. These findings suggest that HMGB1 could be a potential target for therapeutic intervention in SAKI. Lactate promotes the lactylation modification of HMGB1 in macrophages through H3K18lac, facilitating the secretion of HMGB1. After HMGB1 enters neutrophils, it induces the leakage of mitochondrial DNA (mtDNA) in neutrophils, activating the cGAS/STING pathway, promoting the formation of neutrophil extracellular traps (NETs), and exacerbating acute kidney injury in sepsis. • Elevated blood lactate levels are associated with increased HMGB1 levels in SAKI • Lactate increases HMGB1 expression, promotes NET formation, and exacerbates SAKI • Lactate promotes HMGB1 lactylation in macrophages • Lactate triggers the release of mitochondrial DNA from neutrophils • Lactate activates the cyclic GMP-AMP synthase/stimulator of interferon genes pathway