Complement activation at injury sites drives the phagocytosis of necrotic cell debris and resolution of liver injury

Abstract

Cells die by necrosis due to excessive chemical or thermal stress, leading to plasma membrane rupture, release of intracellular components and severe inflammation. The clearance of necrotic cell debris is crucial for tissue recovery and injury resolution, however, the underlying mechanisms are still poorly understood, especially in vivo. This study examined the role of complement proteins in promoting clearance of necrotic cell debris by leukocytes and their influence on liver regeneration. We found that independently of the type of necrotic liver injury, either paracetamol (APAP) overdose or thermal injury, complement proteins C1q and (i)C3b were deposited specifically on necrotic lesions via the activation of the classical pathway. Importantly, C3 deficiency led to a significant accumulation of necrotic debris and impairment of liver recovery in mice, which was attributed to decreased phagocytosis of debris by recruited neutrophils in vivo. Monocytes and macrophages also took part in debris clearance, although the necessity of C3 and CD11b was dependent on the specific type of necrotic liver injury. Using human neutrophils, we showed that depletion of C1q or C3 caused a reduction in the volume of necrotic debris that is phagocytosed, indicating that complement promotes effective debris uptake by neutrophils in mice and humans. In summary, complement activation at injury sites is a pivotal event for necrotic debris clearance by phagocytes and determinant for efficient recovery from tissue injury. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/609344v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@14dc246org.highwire.dtl.DTLVardef@d90b1org.highwire.dtl.DTLVardef@9683adorg.highwire.dtl.DTLVardef@19f13c8_HPS_FORMAT_FIGEXP M_FIG C_FIG Key pointsO_LIThe complement cascade is activated on necrotic cell debris in vivo via the classical pathway C_LIO_LIDeficiency in complement C3 impairs necrotic debris clearance and liver recovery after injury C_LIO_LIComplement-mediated debris clearance is performed by neutrophils, monocytes and macrophages C_LIO_LIHuman neutrophils depend on complement opsonization to phagocytose necrotic cell debris efficiently C_LI