Natural antibodies as “eat-me” signals for phagocytosis of necrotic cell debris at sites of tissue injury

Abstract

SummaryNatural antibodies (NAbs) are circulating polyreactive immunoglobulins that bind endogenous and exogenous antigens. Here, we investigated the role of NAbs in driving the clearance of necrotic cell debris from injury sites. Using mouse models of liver injury, we observed that IgM and IgG NAbs opsonize necrotic debrisin vivoby recognizing common self-molecules such as histones, actin, phosphoinositides and cardiolipin, but not phosphatidylserine. Importantly, mice lacking NAbs presented impaired recovery from liver injury, which was correlated to sustained presence of necrotic debris in the tissue, prolonged inflammation and reduced hepatocellular proliferation. Mechanistically, necrotic debris phagocytosis was dependent on NAbsin vitroandin vivo, and restitution with total immunoglobulins rescued the defective recovery from liver injury in immunodeficient mice. In summary, we showed that NAbs opsonize necrotic cell debris and act as “eat-me” signals for engulfment through FcγRs and CD11b, driving the recovery from tissue injury.HighlightsNatural antibodies opsonize exposed self-antigens upon necrotic cell death.The phagocytosis of necrotic cell debris requires natural antibodies, FcγRs and CD11b.Natural antibodies drive cellular proliferation and tissue regeneration after liver injury.Treatment with natural antibodies improves the recovery from liver injury in both immunodeficient and immunocompetent mice.Graphical abstract