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

Nao Nishikoba,Kotaro Kumagai,Shuji Kanmura,Hirohito Tsubouchi,Mayumi Ono,Hiromi Eguchi,Seiichi Mawatari,Kohei Oda,Tomomi Kamibayashiyama,Shinichi Hashimoto,Yuko Nakamura,Akio Ido,Shiroh Tanoue

doi:10.3389/fimmu.2020.02135

Nao Nishikoba, Kotaro Kumagai + Show 11 more

Open Access

https://doi.org/10.3389/fimmu.2020.02135

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Abstract

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-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.Results: 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 Arg-1 mRNA and secretion of IL-10 and TGF-β1 and downregulated the mRNA expression of iNOS, TNF-α, and IL-6. 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.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.

Highlights

Hepatocyte Growth Factor (HGF) from blood plasma of patients with fulminant hepatic failure has been discovered to be a factor that strongly stimulates DNA synthesis in hepatocytes [1]
M1 macrophages significantly upregulated mRNA expression of the M1 markers iNOS, CD86, TNF-α, and IL6. mRNA expression of the M2 markers Arg-1 and CD206 was significantly upregulated in M2 macrophages, but mRNA expression of IL-10 was significantly upregulated in M1 macrophages (Figure 1A)
Though the spontaneous secretion of TNF-α, IL-6, and IL-10 was significantly increased in the cell culture supernatant of M1 macrophages, TGFβ1 secretion was significantly increased in M2 macrophages (Figure 1B). c-Met expression was significantly upregulated in M1 macrophages

Summary

Introduction

Hepatocyte Growth Factor (HGF) from blood plasma of patients with fulminant hepatic failure has been discovered to be a factor that strongly stimulates DNA synthesis in hepatocytes [1]. HGF-MET signaling is known to promote angiogenesis, cellular motility, growth, invasion, morphological differentiation, embryological development, tissue regeneration, and wound healing in various organs [6]. Based on these data, we attempted to use HGF in clinical treatment and confirmed its safety for acute liver failure patients in a coma [7]. Further work on HGFMET signaling is necessary in several areas to realize the clinical potential of HGF. One of these areas is its impact on immune cells

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