Impaired BCAA catabolism in macrophages exacerbates sepsis-induced lung injury by modulating mitochondrial AGE-RAGE and mtDNA release.

Abstract

Although macrophage immunometabolism is a key contributor to the progression of sepsis-induced acute lung injury, the specific role of branched-chain amino acid (BCAA) catabolism in this process remains unclear. Here, we hypothesized that defective BCAA catabolism in macrophages exacerbates lung injury through activation of the advanced glycation end products (AGEs)-RAGE axis and mitochondrial DNA (mtDNA)-mediated inflammation. We employed a myeloid-specific Pp2cm knockout mouse model to examine the impact of impaired BCAA catabolism on lung injury during sepsis. We found that Pp2cm deficiency upregulated AGEs and their receptor RAGE in macrophages, leading to mitochondrial damage and structural damage. This mitochondrial impairment increased mitochondrial reactive oxygen species production and promoted exosomal mtDNA release, ultimately resulting in aggravated lung injury and higher mortality in myeloid Pp2cm deficient mice subjected to polymicrobial sepsis. Therapeutically, adoptive transfer of bone marrow-derived macrophages from wild-type donors into myeloid Pp2cm deficient mice, restoration of BCAA catabolism using the branched-chain ketoacid dehydrogenase kinase inhibitor BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), inhibition of the AGE-RAGE axis with aminoguanidine, or blockade of exosome release with GW4869 all significantly attenuated lung injury and improved survival. Importantly, in septic patients, PP2Cm expression in peripheral blood mononuclear cells was inversely correlated with radiographic lung injury severity and oxygenation index. Together, these findings identify impaired macrophage BCAA catabolism as a critical driver of sepsis-induced lung injury and highlight the AGE-RAGE axis and mtDNA release as potential therapeutic targets.