Systemic mechanisms of necrotic cell debris clearance

Abstract

Necrosis is an overarching term that describes cell death modalities caused by (extreme) adverse conditions in which cells lose structural integrity. A guaranteed consequence of necrosis is the production of necrotic cell remnants, or debris. Necrotic cell debris is a strong trigger of inflammation, and although inflammatory responses are required for tissue healing, necrotic debris may lead to uncontrolled immune responses and collateral damage. Besides local phagocytosis by recruited leukocytes, there is accumulating evidence that extracellular mechanisms are also involved in necrotic debris clearance. In this review, we focused on systemic clearance mechanisms present in the bloodstream and vasculature that often cooperate to drive the clearance of cell debris. We reviewed the contribution and cooperation of extracellular DNases, the actin-scavenger system, the fibrinolytic system and reticuloendothelial cells in performing clearance of necrotic debris. Moreover, associations of the (mis)functioning of these clearance systems with a variety of diseases were provided, illustrating the importance of the mechanisms of clearance of dead cells in the organism.

Fig. 1. Necrotic cell debris and its phagocytic receptors.

A plethora of damage-associated molecular patterns (DAMPs) are released by necrosis, including nuclear and mitochondrial DNA, RNA, histones, nucleosomes, HMGB1 (high mobility group box 1 protein), actin, N-formylated peptides, ATP (adenosine triphosphate), S100 proteins and HSPs (heat shock proteins). Their clearance is mediated by scavenger and pattern recognition receptors on phagocytes. TLR toll-like receptor, cGAS cyclic GMP-AMP synthase, STING stimulator of interferon genes, AIM2 absent in melanoma 2, ZBP1 Z-DNA-binding protein 1, FPR formyl peptide receptor, CLEC C-type lectin receptor, RAGE receptor for advanced glycation end products, SR scavenger receptor, CD cluster of differentiation, LOX-1 lectin-like oxidized low-density lipoprotein receptor-1, SREC-I scavenger receptor expressed by endothelial cells I, P₂X/Y purinergic P₂X or P₂Y receptors, LRP-1 low-density lipoprotein receptor-related protein-1.

Fig. 2. Overview of the different systemic clearance mechanisms of necrotic cell debris.

Different mechanisms cooperate to facilitate the clearance of necrotic cell debris, as illustrated here by liver injury. These mechanisms include: 1) The removal of necrotic DNA mediated by the circulating deoxyribonucleases DNase 1 and DNase 1L3; 2) Scavenging of necrotic actin by the actin-scavenger system, specifically by vitamin D-binding protein (DBP) and gelsolin; 3) Fibrinolysis by plasmin of the fibrin network bound to necrotic cells; 4) Clearance of circulating necrotic cell debris by the reticuloendothelial system, comprising both the Kupffer cells and the liver sinusoidal endothelial cells (LSECs).

Fig. 3. The interplay between DNases, the actin-scavenger system and the fibrinolytic system during injury.

The interplay between the diverse mechanisms facilitating the clearance of necrotic cell debris is complex. During injury, the actin-scavenger system can become saturated, increasing circulating actin levels. This results in the inhibition of DNase 1 activity, thus impeding the internucleosomal cleavage of necrotic DNA. The activity of the fibrinolytic system, particularly plasmin, can be altered depending on the severity of injury. Plasmin enhances DNase 1 activity while hampering DNase 1L3 activity through the degradation of DNA-binding proteins. Histones and actin can both interact with fibrin, increasing resistance of the fibrin network to fibrinolysis. Additionally, actin acts as a noncompetitive inhibitor of plasmin, further reducing fibrinolysis.

Fig. 4. Proposed mechanisms of debris clearance by the hepatic reticuloendothelial system.

Circulating debris is internalized through endocytosis (LSECs) or phagocytosis (Kupffer cells) in a size-dependent manner by receptors such as CD206, stabilin-1 and -2 and FcγRIIb2 specifically on LSECs. Subsequently, internalized particles are degraded through lysosomal enzymes. LSEC sieve plates facilitate macromolecule internalization. Conflicting reports exist on CD206 expression on Kupffer cells. *: Other receptors, including those listed in Table 4.