Details

Autor(en) / Beteiligte

• Irizarry-Caro, Ricardo A.
• McDaniel, Margaret M.
• Overcast, Garrett R.
• Jain, Viral G.
• Troutman, Ty Dale
• Pasare, Chandrashekhar

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2020-12, Vol.117 (48), p.30628-30638

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• Macrophages respond to microbial ligands and various noxious cues by initiating an inflammatory response aimed at eliminating the original pathogenic insult. Transition of macrophages from a proinflammatory state to a reparative state, however, is vital for resolution of inflammation and return to homeostasis. The molecular players governing this transition remain poorly defined. Here, we find that the reparative macrophage transition is dictated by B-cell adapter for PI3K (BCAP). Mice harboring a macrophage-specific deletion of BCAP fail to recover from and succumb to dextran sulfate sodium-induced colitis due to prolonged intestinal inflammation and impaired tissue repair. Following microbial stimulation, gene expression in WT macrophages switches from an early inflammatory signature to a late reparative signature, a process that is hampered in BCAP-deficient macrophages. We find that absence of BCAP hinders inactivation of FOXO1 and GSK3β, which contributes to their enhanced inflammatory state. BCAP deficiency also results in defective aerobic glycolysis and reduced lactate production. This translates into reduced histone lactylation and decreased expression of reparative macrophage genes. Thus, our results reveal BCAP to be a critical cell-intrinsic switch that regulates transition of inflammatory macrophages to reparative macrophages by imprinting epigenetic changes.