PMID- 32983173 OWN - NLM STAT- MEDLINE DCOM- 20210503 LR - 20210503 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 11 DP - 2020 TI - HGF-MET Signaling Shifts M1 Macrophages Toward an M2-Like Phenotype Through PI3K-Mediated Induction of Arginase-1 Expression. PG - 2135 LID - 10.3389/fimmu.2020.02135 [doi] LID - 2135 AB - Backgrounds and Aims: 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. Methods and Materials: Bone marrow-derived macrophages (BMDMs) isolated from mice were either polarized to an M1 phenotype by IFN-gamma 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. Results: c-Met was expressed especially in M1 macrophages polarized by treatment with IFN-gamma and LPS. In M1 macrophages, HGF-MET signaling induced the expression of Arg-1 mRNA and secretion of IL-10 and TGF-beta1 and downregulated the mRNA expression of iNOS, TNF-alpha, and IL-6. In addition, activation of the PI3K pathway and inactivation of NFkappaB 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-alpha and IL-6 expression. The inactivation of NFkappaB 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. Conclusion: 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. CI - Copyright (c) 2020 Nishikoba, Kumagai, Kanmura, Nakamura, Ono, Eguchi, Kamibayashiyama, Oda, Mawatari, Tanoue, Hashimoto, Tsubouchi and Ido. FAU - Nishikoba, Nao AU - Nishikoba N AD - Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Kumagai, Kotaro AU - Kumagai K AD - Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Kanmura, Shuji AU - Kanmura S AD - Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Nakamura, Yuko AU - Nakamura Y AD - Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Ono, Mayumi AU - Ono M AD - Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Eguchi, Hiromi AU - Eguchi H AD - Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Kamibayashiyama, Tomomi AU - Kamibayashiyama T AD - Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Oda, Kohei AU - Oda K AD - Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Mawatari, Seiichi AU - Mawatari S AD - Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Tanoue, Shiroh AU - Tanoue S AD - Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Hashimoto, Shinichi AU - Hashimoto S AD - Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Tsubouchi, Hirohito AU - Tsubouchi H AD - Department of Gastroenterology and Hepatology, Kagoshima City Hospital, Kagoshima, Japan. FAU - Ido, Akio AU - Ido A AD - Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200902 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (CCAAT-Enhancer-Binding Protein-beta) RN - 0 (Cebpb protein, mouse) RN - 0 (Chromones) RN - 0 (Creb1 protein, mouse) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (HGF protein, mouse) RN - 0 (Lipopolysaccharides) RN - 0 (Morpholines) RN - 0 (Protein Kinase Inhibitors) RN - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 67256-21-7 (Hepatocyte Growth Factor) RN - 82115-62-6 (Interferon-gamma) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-met) RN - EC 3.5.3.1 (Arg1 protein, mouse) RN - EC 3.5.3.1 (Arginase) SB - IM MH - Animals MH - Arginase/*biosynthesis/genetics MH - CCAAT-Enhancer-Binding Protein-beta/metabolism MH - Cell Differentiation MH - Cells, Cultured MH - Chromones/pharmacology MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Gene Expression Regulation MH - Hepatocyte Growth Factor/*physiology MH - Interferon-gamma/pharmacology MH - Lipopolysaccharides/pharmacology MH - Macrophages/classification/drug effects/enzymology/*immunology MH - Mice MH - Mice, Inbred C57BL MH - Morpholines/pharmacology MH - Phenotype MH - Phosphatidylinositol 3-Kinases/*physiology MH - Phosphorylation MH - Protein Kinase Inhibitors/pharmacology MH - Protein Processing, Post-Translational MH - Proto-Oncogene Proteins c-met/biosynthesis/genetics/*physiology MH - Specific Pathogen-Free Organisms PMC - PMC7492554 OTO - NOTNLM OT - HGF-MET signaling OT - PI3K pathway OT - arginase-1 OT - macrophage OT - phenotypic alteration EDAT- 2020/09/29 06:00 MHDA- 2021/05/04 06:00 PMCR- 2020/01/01 CRDT- 2020/09/28 05:41 PHST- 2020/05/19 00:00 [received] PHST- 2020/08/06 00:00 [accepted] PHST- 2020/09/28 05:41 [entrez] PHST- 2020/09/29 06:00 [pubmed] PHST- 2021/05/04 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2020.02135 [doi] PST - epublish SO - Front Immunol. 2020 Sep 2;11:2135. doi: 10.3389/fimmu.2020.02135. eCollection 2020.