Natural antibodies are required for clearance of necrotic cells and recovery from acute liver injury
Matheus Silvério Mattos, Sofie Vandendriessche, Sara Schuermans, Lars Feyaerts, Nadine Hövelmeyer, Ari Waisman, Pedro Elias Marques
Abstract
Background & aimsHepatocellular necrosis is common in both acute and chronic liver injury and may evolve to fibrosis and liver failure. Injury leads to accumulation of necrotic cell debris in the liver, which drives persistent inflammation and poor recovery. This study investigated the role of natural antibodies (NAbs) in the clearance of necrotic cells in the injured liver, its impact on tissue regeneration and the potential of NAbs as a therapy for acute liver injury.MethodsWe used murine models of drug-induced liver injury and focal thermal injury in immunocompetent and antibody-deficient mice (RAG2-/- and IgMi). Intravital microscopy was used to investigate the role of NAbs in the phagocytosis of necrotic cells in the liver in vivo. Immunostainings were used to quantify the extent of liver necrosis (fibrin), antibody deposition (IgM and IgG) and cellular proliferation (Ki67).ResultsBoth IgM and IgG NAbs bound necrotic liver areas and opsonized multiple debris molecules released during hepatocellular necrosis such as DNA, histones, actin, phosphoinositides and mitochondrial cardiolipin, but not phosphatidylserine. RAG2-/- and IgMi mice presented impaired recovery from liver injury, which was correlated to sustained presence of necrotic debris in the tissue, prolonged inflammation and reduced hepatocellular proliferation. These defects were rescued by treating mice with NAbs after induction of injury. Mechanistically, necrotic debris phagocytosis was dependent on NAbs in vitro and in vivo via Fcγ receptors and CD11b. Importantly, supplementation of immunocompetent mice with NAbs also improved liver regeneration significantly, demonstrating the therapeutic potential of natural IgM and IgG.ConclusionNAbs drive the phagocytosis of necrotic cells in liver injury and promote liver regeneration and recovery.Impact and implicationsTreatment with natural antibodies after acute liver injury improved recovery by increasing the clearance of necrotic debris and by improving cellular proliferation in the liver. This preclinical study provides a basis for the development of an immunotherapy for patients with early-stage, reversible, liver injury that aims to prevent disease chronification into fibrosis and liver failure.