Macrophage in liver Fibrosis: Identities and mechanisms

Liver fibrosis is a chronic disease characterized by the deposition of extracellular matrix and continuous loss of tissues that perform liver functions. Macrophages are crucial modulators of innate immunity and play important roles in liver fibrogenesis. Macrophages comprise heterogeneous subpopulations that exhibit different cellular functions. Understanding the identity and function of these cells is essential for understanding the mechanisms of liver fibrogenesis. According to different definitions, liver macrophages are divided into M1/M2 macrophages or monocyte-derived macrophages/Kupffer cells. Classic M1/M2 phenotyping corresponds to pro- or anti-inflammatory effects, and, therefore, influences the degree of fibrosis in later phases. In contrast, the origin of the macrophages is closely associated with their replenishment and activation during liver fibrosis. These two classifications of macrophages depict the function and dynamics of liver-infiltrating macrophages. However, neither description properly elucidates the positive or negative role of macrophages in liver fibrosis. Critical tissue cells mediating liver fibrosis include hepatic stellate cells and hepatic fibroblasts, with hepatic stellate cells being of particular interest because of their close association with macrophages in liver fibrosis. However, the molecular biological descriptions of macrophages are inconsistent between mice and humans, warranting further investigations. In liver fibrosis, macrophages can secrete various pro-fibrotic cytokines, such as TGF-β, Galectin-3 and interleukins (ILs), and fibrosis-inhibiting cytokines, such as IL10. These different secretions may be associated with the specific identity and spatiotemporal characteristics of macrophages. Furthermore, during fibrosis dissipation, macrophages may degrade extracellular matrix by secreting matrix metalloproteinases (MMPs). Notably, using macrophages as therapeutic targets in liver fibrosis has been explored. The current therapeutic approaches for liver fibrosis can by categorized as follows: treatment with macrophage-related molecules and macrophage infusion therapy. Although there have been limited studies, macrophages have shown reliable potential for liver fibrosis treatment. In this review, we focu on the identity and function of macrophages and their relationship to the progression and regression of liver fibrosis.