Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

Abstract

Macrophages, which are key cellular components of the liver, have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. Upon liver injury, resident Kupffer cells (KCs) sense disturbances in homeostasis, interact with hepatic cell populations and release chemokines to recruit circulating leukocytes, including monocytes, which subsequently differentiate into monocyte-derived macrophages (MoMϕs) in the liver. Both KCs and MoMϕs contribute to both the progression and resolution of tissue inflammation and injury in various liver diseases. The diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver diseases. In this review, we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.

Macrophages in Chronic Liver Failure: Diversity, Plasticity and Therapeutic Targeting

“…Innate immune cells (mainly neutrophils, monocytes and macrophages) are primed to detect tissue damaging or infectious insults, and therefore are key orchestrators of inflammatory responses. During progression of CLD these cells initiate and drive both liver and systemic inflammation by recognising/responding to damage-associated molecular patterns (DAMPs) released from injured/activated liver cells and/or pathogen-associated molecular patterns (PAMPs) (16). Fibrosis occurs following chronic liver injury from an insult (toxic, metabolic, or infectious) which can perpetuate inflammation.…”

“…Circulating monocytes, a key component of the mononuclear phagocyte immune system, play pivotal roles in defence against infections and contribute to the systemic inflammation in chronic liver failure. In addition, they augment the local macrophage pool via their recruitment to inflammatory sites after a sterile/tissue-damaging or infectious insult to the liver (10,16,25). Human monocytes are divided into three major subsets: classical (CD14 + CD16 − ), intermediate (CD14 + CD16 + ) and nonclassical (CD14 dim CD16 + ).…”

“…Macrophages are the most abundant hepatic immune cells with pivotal roles: from maintaining liver homeostasis and immune tolerance in the face of continuous exposure to harmless gutderived antigens from food and commensal microbes or their products, to rapidly identifying pathogens and orchestrating immune responses for their elimination (16). In addition, they are functionally important for clearing cellular debris and metabolic waste, and regulating iron and cholesterol homeostasis (16). During steady state, the predominant macrophage population comprises resident Kupffer cells (KCs) which are capable of self-renewal and have a specific transcriptional program defined by their unique niche (44)(45)(46).…”

Controversies and Opportunities in the Use of Inflammatory Markers for Diagnosis or Risk Prediction in Fatty Liver Disease

“…This recruitment of pro-inflammatory cells, which significantly changes the immune cell composition of the liver during NAFLD, may occur via various chemoattractant-axes, including the CCL2/CCR2, CCL1/CCR8, CXCR6/CXCL16, and CCL25/CCR9-pathways, with the chemoattractants being secreted by activated Kupffer cells, liver sinusoidal endothelial cells, and hepatic stellate cells. Besides the enhanced recruitment, also an enhanced polarization of macrophages toward a pro-inflammatory (“M1-like”) phenotype can be observed, potentially caused by stimulating cytokines such as TNF and IFN-γ ( 30 , 32 ).…”

“…Many experimental studies revealed that the “sterile” inflammation observed during NAFLD leads to a perpetuation of liver disease. Indeed, studies depleting certain types of immune cells ( 36 , 37 ), or blocking the polarization and recruitment of inflammatory cells, have led to significant alleviation of fibrosis in various mouse models and early-stage clinical trials ( 32 ). However, it should not be forgotten that the inflammatory response is also crucial for healing and tissue repair, often observed during the early stages of liver injury ( 38 ).…”