Hepatic macrophages: Key players in the development and progression of liver fibrosis

Abstract

Hepatic fibrosis is a common pathological process involving persistent liver injury with various etiologies and subsequent inflammatory responses that occur in chronic liver diseases. If left untreated, liver fibrosis can progress to liver cirrhosis, hepatocellular carcinoma and eventually, liver failure. Unfortunately, to date, there is no effective treatment for liver fibrosis, with the exception of liver transplantation. Although the pathophysiology of liver fibrosis is multifactorial and includes the activation of hepatic stellate cells, which are known to drive liver fibrogenesis, hepatic macrophages have emerged as central players in the development of liver fibrosis and regression. Hepatic macrophages, which consist of resident macrophages (Kupffer cells) and monocyte‐derived macrophages, have been shown to play an intricate role in the initiation of inflammatory responses to liver injury, progression of fibrosis, and promotion of fibrosis resolution. These features have made hepatic macrophages uniquely attractive therapeutic targets in the fight against hepatic fibrosis. In this review, we synthesised the literature to highlight the functions and regulation of heterogeneity in hepatic macrophages. Furthermore, using the existing findings, we attempt to offer insights into the molecular mechanisms underlying the phenotypic switch from fibrogenic macrophages to restorative macrophages, the regulation of heterogeneity, and modes of action for hepatic macrophages. A better understanding of these mechanisms may guide the development of novel anti‐fibrotic therapies (eg macrophage subset‐targeted treatments) to combat liver fibrosis in the future.

Is the Macrophage Phenotype Determinant for Fibrosis Development?

“…As it occurs in other scenarios, fibrogenesis starts as a defensive wound-healing mechanism, but becomes a persistent and pathogenic dysregulated tissue repair that leads to fibrillar connective tissue and fibrotic scar deposition, which accumulate in the liver parenchyma, disrupting its architecture and function and impeding tissue regeneration. If this fibrotic process continues, cirrhosis development becomes imminent, which may also lead to hepatocellular carcinoma and even liver failure [ 97 ].…”

“…As immune cells, they regulate hepatic homeostasis and participate in the first steps of the inflammatory response to liver damage. In addition, they show a dual role participating in both the evolution of liver fibrosis and scar tissue degradation, and subsequent fibrosis resolution [ 97 ]. In the liver, two main types of macrophages can be distinguished.…”

“…In murine studies, they are classified according to the expression of Ly6C. Those that express Ly6C are recognized as Ly6C high and are described as pro-inflammatory mediators, while those that do not express Ly6C are recognized as Ly6C low and have been defined as restorers of tissue integrity [ 96 , 97 ].…”

“…Indeed, the most described action driven by macrophages that contributes to liver fibrosis is the activation of HSCs [ 94 , 95 , 101 ]. Liver macrophages can receive a wide variety of stimuli, which induces the secretion of certain substances that in turn activate the pro-fibrotic role of HSCs in remodeling the immune microenvironment and promoting ECM deposition [ 97 ]. Experimentally, it has been demonstrated that the removal of macrophages by using different techniques, such as genetic (LysM, myeloid-specific) models or clodronate liposomes in murine models, reduces liver injury and inflammation [ 102 , 103 ].…”

“…As we have seen in several examples before, apart from resident macrophages, other types of macrophages can be recruited to the site of injury in the liver, potentiating fibrosis as a result [ 97 ]. In a CCl4-fibrosis murine model, BMDMs were found to be recruited via cannabinoid receptor 1 (CB1), which has also been demonstrated to be involved in the expression of pro-fibrotic and pro-inflammatory cytokines [ 123 ].…”