HGF-MET Signaling Shifts M1 Macrophages Toward an M2-Like Phenotype Through PI3K-Mediated Induction of Arginase-1 Expression

• Published in: Frontiers in immunology 2020-09, Vol.11, p.2135-2135
• Main Authors: Nishikoba, Nao, Kumagai, Kotaro, Kanmura, Shuji, Nakamura, Yuko, Ono, Mayumi, Eguchi, Hiromi, Kamibayashiyama, Tomomi, Oda, Kohei, Mawatari, Seiichi, Tanoue, Shiroh, Hashimoto, Shinichi, Tsubouchi, Hirohito, Ido, Akio
• Format: Article
• Language: English
• Subjects: Animals; Arginase - biosynthesis; Arginase - genetics; arginase-1; CCAAT-Enhancer-Binding Protein-beta - metabolism; Cell Differentiation; Cells, Cultured; Chromones - pharmacology; Cyclic AMP Response Element-Binding Protein - metabolism; Gene Expression Regulation; Hepatocyte Growth Factor - physiology; HGF-MET signaling; Immunology; Interferon-gamma - pharmacology; Lipopolysaccharides - pharmacology; macrophage; Macrophages - classification; Macrophages - drug effects; Macrophages - enzymology; Macrophages - immunology; Mice; Mice, Inbred C57BL; Morpholines - pharmacology; Phenotype; phenotypic alteration; Phosphatidylinositol 3-Kinases - physiology; Phosphorylation; PI3K pathway; Protein Kinase Inhibitors - pharmacology; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-met - biosynthesis; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - physiology; Specific Pathogen-Free Organisms
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.02135

Hepatocyte Growth Factor (HGF)-MET signaling is known to promote biological functions such as cell survival, cell motility, and cell proliferation. However, it is unknown if HGF-MET alters the macrophage phenotype. In this study, we aimed to study the effects of HGF-MET signaling on the M1 macrophage phenotype. Bone marrow-derived macrophages (BMDMs) isolated from mice were either polarized to an M1 phenotype by IFN-γ and LPS treatment or to an M2 phenotype by IL-4 treatment. Changes in M1 or M2 markers induced by HGF-MET signaling were evaluated. Mechanisms responsible for alternations in the macrophage phenotype and intracellular metabolism were analyzed. c-Met was expressed especially in M1 macrophages polarized by treatment with IFN-γ and LPS. In M1 macrophages, HGF-MET signaling induced the expression of mRNA and secretion of IL-10 and TGF-β1 and downregulated the mRNA expression of α, and . In addition, activation of the PI3K pathway and inactivation of NFκB were also observed in M1 macrophages treated with HGF. The increased Arg-1 expression and IL-10 secretion were abrogated by PI3K inhibition, whereas, no changes were observed in TNF-α and IL-6 expression. The inactivation of NFκB was found to be independent of the PI3K pathway. HGF-MET signaling shifted the M1 macrophages to an M2-like phenotype, mainly through PI3K-mediated induction of Arg-1 expression. Finally, HGF-MET signaling also shifted the M1 macrophage intracellular metabolism toward an M2 phenotype, especially with respect to fatty acid metabolism. Our results suggested that HGF treatment not only promotes regeneration in epithelial cells, but also leads to tissue repair by altering M1 macrophages to an M2-like phenotype.