Liver Injury and the Macrophage Issue: Molecular and Mechanistic Facts and Their Clinical Relevance

Abstract

The liver is an essential immunological organ due to its gatekeeper position to bypassing antigens from the intestinal blood flow and microbial products from the intestinal commensals. The tissue-resident liver macrophages, termed Kupffer cells, represent key phagocytes that closely interact with local parenchymal, interstitial and other immunological cells in the liver to maintain homeostasis and tolerance against harmless antigens. Upon liver injury, the pool of hepatic macrophages expands dramatically by infiltrating bone marrow-/monocyte-derived macrophages. The interplay of the injured microenvironment and altered macrophage pool skews the subsequent course of liver injuries. It may range from complete recovery to chronic inflammation, fibrosis, cirrhosis and eventually hepatocellular cancer. This review summarizes current knowledge on the classification and role of hepatic macrophages in the healthy and injured liver.

Is the Macrophage Phenotype Determinant for Fibrosis Development?

“…The disease state and the differentiation status of macrophages are crucial to determine whether macrophages are playing a pro-fibrotic role or, in contrast, exerting anti-fibrogenic activity [94]. In this case, as previously described, it has been extensively demonstrated in murine models that macrophages of the Ly6C low phenotype contribute to collagen breakdown and regression of ECM deposition [96,109,127]. An example of macrophages that have this phenotype are CD11b high /F4/80 intermediate LY6C low macrophages [95].…”

“…[128] TREM2+CD9+ MMP-13 Fibrosis resolution and inflammation restoration through MIF [129,130] SAMs MMP-2 and MMP-14 increase and TIMP-1 and TIMP-2 inhibition Fibrosis resolution [131] Ly6C high ↓ Ly6C low STAT-3-IL-10-IL-6 axis Switching from the pro-fibrotic Ly6C high phenotype to the pro-restorative Ly6C low [133] PtdSer-dependent RTKs and MERTK [134] CD5L [135] stabilin-1 [136] Interestingly, certain murine model studies have revealed the possibility of switching from the pro-fibrotic Ly6C high phenotype to the pro-restorative Ly6C low through different molecular pathways [96]. One of the most described pathways involves the STAT-3-IL-10-IL-6 axis [133].…”

“…Liver fibrosis is the result of the continuous and progressive activation of different liver-resident and infiltrating immune cells, which occurs in response to acute or chronic cell injury, and which perpetuates inflammation [ 94 , 95 ]. Chronic liver injury may arise as a response to the aggression of toxics such as alcohol, infections, or fat accumulation, which characterize alcoholic liver disease, viral hepatitis, or non-alcoholic fatty liver diseases, among others [ 96 ]. 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.…”

Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression

“…However, this traditionally classification based on induction of in vitro polarization does not well describe the phenotypic heterogeneity of hepatic macrophage in vivo [109]. In murine models, Ly6c expression is used to characterize populations of circulating monocytes and macrophages in pathology [119,122]. Circulating Ly6c + / high and Ly6c − / low monocytes have been well characterized.…”

“…KCs express specific markers useful for their characterization, such as F4/80, CD11b +/low , CD68 and, C-type lectin domain family 4 member F (CLEC4F) in mice [122]. In the early stages of liver damage, KCs exert proinflammatory and protective actions, through the release of cytokines and chemokines, which further recruit other immune cells.…”