TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation

Significance Macrophages initiate inflammation to eliminate invading microbes. Following clearance of inflammatory stimuli, macrophages down-regulate inflammatory genes and express repair genes to protect host tissues from damage. Here, we find that the adaptor B-cell adapter for PI3K (BCAP) facilitates this transition of inflammatory macrophages to reparative macrophages. Absence of BCAP in macrophages limits the ability of mice to repair intestinal tissues following inflammatory damage. Following Toll-like receptor stimulation, macrophages undergo aerobic glycolysis that results in lactate production, a process compromised in BCAP-deficient macrophages. This lactate is incorporated into histone tails and is involved in reparative macrophage transition. We find defective lactate production by BCAP-deficient macrophages results in reduced histone lactylation and expression of tissue repair genes, thus blunting their reparative transition.