ACAT1-Mediated SP1-K694 Lactylation Promotes M1 Macrophage Polarization via TREM1 Transcription in COPD.

Aberrant macrophage polarization is one of the key mechanisms underlying chronic obstructive pulmonary disease (COPD), but the underlying processes have not yet been fully elucidated. Lactylation is a novel lactate-derived post-translational modification and is relatively active in M1 macrophages. This study identified SP1 lactylation at lysine 694 (SP1-K694la), which was elevated in Cigarette Smoke Extract(CSE)-induced macrophages and COPD mice and enhanced SP1 enrichment at the TREM1 promoter. TREM1 knockdown reduced M1 macrophages. The SP1-K694R mutation (mimicking delactylation) decreased SP1-K694la, reduced SP1 enrichment at the TREM1 promoter, and downregulated M1 macrophages under CSE treatment. In contrast, the SP1-K694Q mutation (mimicking constitutive lactylation) increased SP1-K694la, enhanced SP1 enrichment at the TREM1 promoter, and promoted M1 macrophage polarization. Furthermore, TREM1 knockdown alleviated SP1-K694la-mediated increase in M1 macrophages and reduced secretion of IL-1β, IL-6, and TNF-α. In addition, ACAT1 was identified as a lactyltransferase for SP1-K694la. In COPD patients, lactate levels, Pan-Kla, LDHA, SP1-K694la, and TREM1 were elevated. Lactate levels correlated positively with smoking index and were higher in GOLD 3-4 than in GOLD 1 patients, while TREM1 mRNA correlated negatively with FEV1, FEV1%pred, and FEV1/FVC.ACAT1 acts as a lactyltransferase, increasing SP1-K694la to enhance TREM1 transcription, which promotes M1 polarization and airway inflammation in COPD.