biostudies-literatureNgai DAmerican Heart AssociationNCRR NIH HHSNHLBI NIH HHSNCI NIH HHSNIH HHSU.S. Department of Health & Human Services | National Institutes of Health2206-2219https://www.ebi.ac.uk/biostudies/studies/S-EPMC10782856biostudies-literatureUnknown5(12)The clearance of apoptotic cells by macrophages (efferocytosis) prevents necrosis and inflammation and activates pro-resolving pathways, including continual efferocytosis. A key resolution process in vivo is efferocytosis-induced macrophage proliferation (EIMP), in which apoptotic cell-derived nucleotides trigger Myc-mediated proliferation of pro-resolving macrophages. Here we show that EIMP requires a second input that is integrated with cellular metabolism, notably efferocytosis-induced lactate production. Lactate signalling via GPR132 promotes Myc protein stabilization and subsequent macrophage proliferation. This mechanism is validated in vivo using a mouse model of dexamethasone-induced thymocyte apoptosis, which elevates apoptotic cell burden and requires efferocytosis to prevent inflammation and necrosis. Thus, EIMP, a key process in tissue resolution, requires inputs from two independent processes: a signalling pathway induced by apoptotic cell-derived nucleotides and a cellular metabolism pathway involving lactate production. These findings illustrate how seemingly distinct pathways in efferocytosing macrophages are integrated to carry out a key process in tissue resolution.Nature metabolismEfferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair.PMC10782856S10 OD020056S10 RR027050R35-HL145228P01 HL087123900337R35 HL145228P30 CA013696Schilperoort MTabas INgai DfalseEfferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair.The clearance of apoptotic cells by macrophages (efferocytosis) prevents necrosis and inflammation and activates pro-resolving pathways, including continual efferocytosis. A key resolution process in vivo is efferocytosis-induced macrophage proliferation (EIMP), in which apoptotic cell-derived nucleotides trigger Myc-mediated proliferation of pro-resolving macrophages. Here we show that EIMP requires a second input that is integrated with cellular metabolism, notably efferocytosis-induced lactate production. Lactate signalling via GPR132 promotes Myc protein stabilization and subsequent macrophage proliferation. This mechanism is validated in vivo using a mouse model of dexamethasone-induced thymocyte apoptosis, which elevates apoptotic cell burden and requires efferocytosis to prevent inflammation and necrosis. Thus, EIMP, a key process in tissue resolution, requires inputs from two independent processes: a signalling pathway induced by apoptotic cell-derived nucleotides and a cellular metabolism pathway involving lactate production. These findings illustrate how seemingly distinct pathways in efferocytosing macrophages are integrated to carry out a key process in tissue resolution.2023-01-01T00:00:00Z2023 Dec2025-04-04T01:17:59.256Z2025-04-04T01:17:59.256ZS-EPMC107828563801241410.1038/s42255-023-00921-9