Lactate Ringer’s anti-inflammatory effects in acute pancreatitis are potentially mediated by protein lactylation of extracellular vesicles

Abstract

Abstract Lactated Ringer’s solution (LR) has been associated with anti-inflammatory effects in acute pancreatitis, likely attributable to its lactate content, but the underlying mechanisms remain poorly understood. Circulating small extracellular vesicles (sEVs) contribute to systemic inflammation in this condition by activating macrophages, and we investigated whether lactate could modulate their inflammatory activity. sEVs derived from BxPC-3 pancreatic cells were treated with lactate and their inflammatory potential assessed by measuring their capacity to induce pro-inflammatory cytokine expression in macrophages. Circulating sEVs were also isolated from patients with acute pancreatitis receiving either LR or normal saline and analysed using the same approach. Vesicle uptake and protein lactylation levels were evaluated by microscopy and western blot, respectively. Lactate treatment reduced sEV-induced macrophage activation without altering vesicle uptake, and was associated with a modest increase in protein lactylation. A similar reduction in inflammatory activity was observed in circulating sEVs from LR-treated patients, but not in those receiving normal saline, alongside a comparable increase in protein lactylation. These findings suggest that lactate can directly modify sEV activity and that the anti-inflammatory effects of LR in acute pancreatitis may be mediated, at least in part, through lactylation-dependent modulation of sEV inflammatory activity.