Malondialdehyde epitopes exposed on dying cells are potent modulators of complement activity and efferocytosis

Multicellular organisms rely on efficient removal of dying cells to maintain tissue homeostasis. However, during severe tissue damage, when clearance mechanisms are overwhelmed, uncleared dying cells expose various danger-associated molecular patterns (DAMPs), such as malondialdehyde (MDA)- epitopes, which further propagate disease-associated sterile inflammation. MDA-epitopes are present on the surface of dying cells and are specifically recognized by several complement proteins, but the precise nature of their membrane exposure nor whether, and how, this interaction contributes to the removal of dead cells is unknown. Here, we demonstrate that MDA-epitopes were detected on the surfaces of dying cells generated by extrinsic or intrinsic triggers of apoptosis, ferroptosis, and necroptosis, and their occurrence was associated with loss of membrane integrity. Moreover, we show that MDA adducts activate the classical complement pathway by directly binding natural IgM antibodies and C1q and regulate the extent of complement activation through MDA-dependent preferential recruitment of the acute-phase variant of C4b-binding protein (C4BP (α6β0)). This MDA-epitope-guided and C4BP-tuned opsonization of dying cells with IgM, C1q, C4b, and C3b modulates their clearance by phagocytes in human and murine in vitro assays. Our findings identify MDA-epitopes as key mediators in recognizing and clearing dying cells, linking oxidative stress to immune activation and tissue homeostasis.