Efferocytosis in liver disease

Abstract

The process of dead cell clearance by phagocytic cells, called efferocytosis, prevents inflammatory cell necrosis and promotes resolution and repair. Defective efferocytosis contributes to the progression of numerous diseases in which cell death is prominent, including liver disease. Many gaps remain in our understanding of how hepatic macrophages carry out efferocytosis and how this process goes awry in various types of liver diseases. Thus far, studies have suggested that, upon liver injury, liver-resident Kupffer cells and infiltrating monocyte-derived macrophages clear dead cells, limit inflammation, and, through macrophage reprogramming, repair liver damage. However, in unusual settings, efferocytosis can promote liver disease. In this review, we will focus on efferocytosis in various types of acute and chronic liver diseases, including metabolic dysfunction-associated steatohepatitis. Understanding the mechanisms and consequences of efferocytosis by hepatic macrophages has the potential to shed new light on liver disease pathophysiology and to guide new treatment strategies to prevent disease progression.

Keywords: Kupffer cells; acute liver injury; apoptotic cells; hepatic stellate cells; liver fibrosis; liver inflammation; macrophages; metabolic dysfunction-associated steatohepatitis (MASH); tissue resolution.

Fig. 1

Fundamentals of efferocytosis. Phagocytes, particularly MΦs, capture ACs through recognition of signals on the ACs, notably PS, by receptors, e.g., MerTK, TIM4, and TREM2. AC internalisation and phagolysosomal degradation clear tissues of dead cells, which prevents necrosis and inflammation. In addition, efferocytosis reprogrammes MΦs into a pro-resolving phenotype driven by efferocytosis receptor signalling and pathways triggered by the degraded AC cargo, e.g. amino acids, lipids, and nucleic acids. The reprogrammed MΦs secreted resolution mediators, e.g. interleukin-10, that both repair tissues and further stimulate efferocytosis. The figure was generated using Biorender.com. ACs, apoptotic cells; MΦs, macrophages; PS, phosphatidylserine; MerTK, MER proto-oncogene, tyrosine kinase; TIM4, T cell immunoglobulin and mucin domain containing 4; TREM2, Triggering receptor expressed on myeloid cells 2; LRP1, LDL receptor related protein 1; BAI1, Adhesion G protein-coupled receptor B1.

Fig. 2

Proposed roles of efferocytosis in liver disease. (Left) Examples of clearance of dead hepatocytes, neutrophils, and cholangiocytes, mostly by various types of hepatic MΦ, which are proposed to become defective in liver disease and thereby promote disease progression. (Right) In certain types of liver disease, mostly in vitro studies have suggested that efferocytosis by HSCs promotes their activation, leading to pathologic liver fibrosis. Clearance of dead neutrophils by a subpopulation of hepatic MΦs may also be pathogenic. As explained in the text, many of these processes should be considered hypotheses awaiting further proof in vivo. The figure was generated using Biorender.com. ALI, acute liver injury; ALD, alcohol-related liver disease; CLD, cholestatic liver disease; DILI, drug-induced liver injury; HC, hepatocyte; HIV, human immunodeficiency virus; HSC, hepatic stellate cell; IRI, ischaemia-reperfusion injury; KC, Kupffer cell; MASH, metabolic dysfunction-associated steatohepatitis; MΦs, macrophages; VH, viral hepatitis; MerTK, MER proto-oncogene, tyrosine kinase; SIRPα, Signal-regulatory protein alpha; Ly6C, Ly6-C antigen; ASGPR, Asialoglycoprotein receptor 1; FABP4, Fatty acid binding protein 4; TIM4, T cell immunoglobulin and mucin domain containing 4; TREM2, Triggering receptor expressed on myeloid cells 2; MMP, Matrix metalloproteinase; MFGE8, Milk fat globule EGF and factor V/VIII domain containing; CCN1, Cellular communication network factor 1.