Efferocytosis Remodels Osteoclast Metabolism and Enhances Antibacterial Defense

Abstract

Osteoclasts are metabolically specialized for bone resorption, but how apoptotic-cell uptake shapes their immune function remains unclear. During Staphylococcus aureus bone infection, osteoclasts engulfed apoptotic neutrophils. In osteoclast cultures, apoptotic-neutrophil exposure reduced multinucleation and resorption, induced host-defense programs, and enhanced antibacterial activity, whereas macrophages showed no comparable antibacterial response. MERTK was required for efficient osteoclast efferocytosis. Ctsk-Cre-mediated Mertk deletion increased bacterial burden and bone loss, whereas transplantation of MERTK-competent bone marrow restored osteoclast efferocytosis and reduced infection-associated bone damage. Transcriptomic and extracellular flux analyses revealed enhanced glycolytic activity and altered lactate handling in efferocytic osteoclasts. Lactate supplementation reduced osteoclast formation without reproducing the antibacterial phenotype. Inhibiting lactate production or export attenuated antibacterial activity in efferocytic osteoclasts, whereas blocking lactate uptake enhanced it. These findings identify osteoclast efferocytosis as an immune adaptation that links apoptotic-neutrophil clearance to metabolic remodeling and antibacterial defense in bone.