Lung Myofibroblasts Promote Macrophage Profibrotic Activity through Lactate-induced Histone Lactylation

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Metabolic Regulation

Background:

• Lung myofibroblast metabolic reprogramming, specifically augmented glycolysis, drives their profibrotic phenotype.
• Lactate, a glycolysis byproduct, is secreted and contributes to the fibrotic niche involving myofibroblasts and macrophages.

Purpose of the Study:

• To investigate the non-cell autonomous effect of myofibroblast glycolysis via lactate on alveolar macrophage phenotype.
• To elucidate the molecular mechanisms by which lactate influences macrophage profibrotic mediator expression.

Main Methods:

• Analysis of lactate levels in conditioned media of TGF-β1-induced lung myofibroblasts and BAL fluids from fibrotic mouse models.
• Assessment of profibrotic mediator expression in macrophages exposed to conditioned media/BAL fluids.
• Investigation of histone lactylation and p300 involvement in lactate-mediated gene expression changes in macrophages.

Main Results:

• Elevated lactate levels were observed in myofibroblast-conditioned media and fibrotic BAL fluids.
• Conditioned media and BAL fluids enhanced profibrotic mediator expression in macrophages.
• Lactate induced histone lactylation in macrophage profibrotic gene promoters, a process dependent on p300.

Conclusions:

• Myofibroblast-derived lactate plays a crucial role in regulating alveolar macrophage phenotype during lung fibrosis.
• Histone lactylation, mediated by p300, is a key epigenetic mechanism linking lactate to profibrotic gene expression in macrophages.
• Metabolites like lactate can mediate intercellular communication in fibrotic diseases, offering new therapeutic targets.