Table 2.

Schematic description of macrophage contribution in oxidative stress, inflammation, and fibrosis. Abbreviations: ROS (reactive oxygen species); RNS (reactive nitrogen species); NADPH (nicotinamide adenine dinucleotide phosphate); TNF-α (tumor necrosis factor-alpha); IL-1β (interleukin-1beta); IL-12 (interleukin-12); IL-6 (interleukin-6); CCL-2 (chemokine C-C motif ligand-2); TGF-β (tumor growth factor-beta); EMT (epithelial mesenchymal transition); ECM (extracellular matrix).

Items	Description
Oxidative stress	Activated macrophages are the major responsible for the oxidative stress. ROS and RNS recombine with macromolecules and lead to the degradation of protein, lipid peroxidation, and oxidation of DNA. NADPH, also called NOX, is the key enzyme for ROS production (e.g., superoxide, hydroxyl and peroxyl radicals). Inducible NO synthase (iNOS) is a key enzyme for RNS production (e.g., nitric oxide and peroxynitrite).
Inflammation	Activated macrophages secrete pro-inflammatory factors. - cytokines: TNF-α; IL-1β; IL-12; IL-6 TNF-α is produced predominantly at sites of inflammation by activated monocytes and macrophages. TNF-α induces hepatocytes apoptosis, and activation of HSCs. In chronic inflammatory hepatopathies, IL-1β is mostly produced by KCs, hepatocytes, and adipocytes. In KCs, it promotes liver inflammation by amplifying inflammasome activation, TNFα, and IL-β release. IL-1β sustains hepatic steatosis by stimulating triglyceride and cholesterol accumulation in primary liver hepatocytes, lipid droplet formation, and insulin resistance in hepatocytes [27,28]. IL-6 dependent signaling in the liver is critical for the induction of the acute-phase response [29]. The main role of IL-12 is to stimulate immune cells and other lymphocytes. - chemokines regulate the migration and functions of KCs, HSCs, hepatocytes, endothelial cells, and the recruitment of circulating immune cells. CCL2, also known as monocyte chemotactic factor 1 (MCP1), is one of the best characterized chemokines in the hepatic fibrogenesis. CCL2 regulates the migration and infiltration of monocytes/macrophages through combination with its specific receptor CCR2 [30]. It has been reported that CCL2/CCR2 axis has a vital role during fibrosis [30].
Fibrosis	Activated macrophages produce high amount of TGF-β [31]. TGF-β sustains oxidative stress, proliferation and activation of HSCs into myofibroblast-like cells, proliferation and differentiation of fibroblasts into myofibroblast, EMT, synthesis of ECM and stimulate the expression of metalloproteinase inhibitors.