Cytokinesis Arrest-induced Binucleation of Macrophages ProducesHighly Efficient Efferocytes

Efferocytosis, the phagocytic clearance of dying cells and debris, supports tissue homeostasis, immune tolerance, and inflammation resolution, whereas its failure contributes to autoimmunity, atherosclerosis, aging, and impaired tissue repair. Although many molecular regulators of efferocytosis have been defined, less is known about whether macrophages can be reprogrammed into a distinct cellular state with intrinsically enhanced efferocytosis capacity. Guided by a CRISPR screen, we found that Pdcd6ip loss induces cytokinesis arrest and binucleation, creating macrophages with superior efferocytic function. Binucleated Pdcd6ip-/- bone marrow-derived macrophages demonstrate a coordinately enhanced multi-corpse capture and processing, and resolution response, and acquired a distinct transcriptomic signature. In vivo, Pdcd6ip deletion enhanced splenic macrophage efferocytosis, reduced autoimmune responses after repeated apoptotic cell challenge, and promoted plaque stability without metabolic or hematologic changes. PDCD6IP perturbation similarly increased binucleation and engulfment in human macrophage-like cells. Thus, incomplete cytokinesis represents an unrecognized route to macrophage specialization with enhanced efferocytosis capacity.