Jiang Jing, Wang Ruiyan, Song Pengli, Peng Qi, Jin Xuerui, Li Bin, Ni Jianbo, Shen Jie, Bao Jingpiao, Wu Zengkai, Ge Xiaolu, Wang Xingpeng, Hu Guoyong
Department of Gastroenterology, Shanghai General Hospital, Shanghai, China; Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Gastroenterology, Shanghai General Hospital, Shanghai, China; Shanghai General Hospital Jiuquan Hospital, Jiuquan, Gansu, China.
Cell Mol Gastroenterol Hepatol. 2025 May 10;19(9):101535. doi: 10.1016/j.jcmgh.2025.101535.
BACKGROUND & AIMS: During acute pancreatitis (AP), glycolysis is enhanced. The upregulation of glycolysis increases the level of metabolite lactate. Lactate has been shown to facilitate tissue repair across various pathologic conditions. However, its role in the recovery following AP remains unclear. This study aims to explore the role of lactate in the regenerative processes following AP and to elucidate its underlying molecular mechanisms.
The caerulein-induced recovery AP model was established using wild-type and 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (Pfkfb3) heterozygous mice. Pancreatic repair was evaluated histologically, whereas lactate levels and inflammatory markers were measured serologically. Macrophages were isolated from pancreatic tissue using fluorescence-activated cell sorting for mRNA sequencing to identify phenotypes. In ex vivo, macrophages were indirectly co-cultured with inflammatory acinar, and the effect of lactate on macrophage phenotype were investigated through immunoprecipitation, fluorescence analysis, and Western blotting.
We first found that exogenous lactate administration promoted pancreatic repair, whereas Pfkfb3 deficiency lowered lactate levels and ultimately delayed pancreatic repair. Mechanistically, lactate altered macrophage phenotype during recovery after AP, by reducing the proportion of pro-inflammatory macrophages and increasing the percentage of reparative macrophages. In the indirectly co-cultured macrophage, lactate increased lactylation levels and enhanced repair gene expression. Treatment with AZD3965, a chemical inhibitor of lactate transportation, blocked the effects on lactylation and gene expression. Besides, lactate repressed the JAK2-STAT1 pathway via GPR132 receptor, thereby suppressing the expression of pro-inflammatory genes.
Lactate facilitates pancreatic repair by promoting reparative macrophage polarization, achieved through promoting lactylation and inhibiting JAK2-STAT1 signaling. This phenotypic shift alleviates inflammation and facilitates tissue recovery, highlighting a potential therapeutic approach for AP.
在急性胰腺炎（AP）期间，糖酵解增强。糖酵解的上调会增加代谢产物乳酸的水平。乳酸已被证明在各种病理状况下可促进组织修复。然而，其在AP恢复过程中的作用仍不清楚。本研究旨在探讨乳酸在AP后再生过程中的作用，并阐明其潜在的分子机制。
使用野生型和6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶3（Pfkfb3）杂合小鼠建立雨蛙肽诱导的AP恢复模型。通过组织学评估胰腺修复情况，而血清学检测乳酸水平和炎症标志物。使用荧光激活细胞分选从胰腺组织中分离巨噬细胞进行mRNA测序以鉴定表型。在体外，将巨噬细胞与炎性腺泡间接共培养，通过免疫沉淀、荧光分析和蛋白质免疫印迹研究乳酸对巨噬细胞表型的影响。
我们首先发现外源性给予乳酸可促进胰腺修复，而Pfkfb3缺乏会降低乳酸水平并最终延迟胰腺修复。机制上，乳酸在AP后的恢复过程中改变了巨噬细胞表型，通过减少促炎巨噬细胞的比例并增加修复性巨噬细胞的百分比。在间接共培养的巨噬细胞中，乳酸增加了乳酰化水平并增强了修复基因的表达。用乳酸转运化学抑制剂AZD3965处理可阻断对乳酰化和基因表达的影响。此外，乳酸通过GPR132受体抑制JAK2-STAT1途径，从而抑制促炎基因的表达。
乳酸通过促进修复性巨噬细胞极化来促进胰腺修复，这是通过促进乳酰化和抑制JAK2-STAT1信号传导实现的。这种表型转变减轻了炎症并促进了组织恢复，突出了一种潜在的AP治疗方法。
