Upregulation of IFN-β induced by Sema4D-dependent partial Erk1/2 inhibition promotes NO production in microglia

Ryo Tsuchihashi; Toshinori Sawano; Fumiya Watanabe; Natsumi Yamaguchi; Wataru Yamaguchi; Kenta Niimi; Satoshi Shibata; Tatsuo Furuyama; Hidekazu Tanaka; Shinobu Inagaki

doi:10.1016/j.bbrc.2019.10.201

Upregulation of IFN-β induced by Sema4D-dependent partial Erk1/2 inhibition promotes NO production in microglia

Biochem Biophys Res Commun. 2020 Jan 22;521(4):827-832. doi: 10.1016/j.bbrc.2019.10.201. Epub 2019 Nov 7.

Authors

Affiliations

¹ Group of Neurobiology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Suita, Japan.
² Group of Neurobiology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Suita, Japan; Laboratory of Pharmacology, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Japan.
³ Laboratory of Pharmacology, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Japan.
⁴ Kagawa Prefectural College of Health Sciences, Takamatsu, Japan.
⁵ Group of Neurobiology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Suita, Japan; Kagawa Prefectural College of Health Sciences, Takamatsu, Japan.
⁶ Group of Neurobiology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Suita, Japan; Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Suita, Japan.
⁷ Group of Neurobiology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Suita, Japan; United Graduate School of Child Development, Osaka University, Suita, Japan; Department of Physical Therapy, Osaka Yukioka College of Health Science, Ibaraki, Japan. Electronic address: inagaki@sahs.med.osaka-u.ac.jp.

PMID: 31708102
DOI: 10.1016/j.bbrc.2019.10.201

Abstract

Interactions between Sema4D and its receptors, PlexinB1 and CD72, induce various functions, including axon guidance, angiogenesis, and immune activation. Our previous study revealed that Sema4D is involved in the upregulation of nitric oxide production in microglia after cerebral ischemia. In this study, we investigated the underlying mechanisms of the enhancement of microglial nitric oxide production by Sema4D. Primary microglia expressed PlexinB1 and CD72, and cortical microglia expressed CD72. Sema4D promoted nitric oxide production and slightly inhibited Erk1/2 phosphorylation in microglia. Partial Erk1/2 inhibition enhanced microglial nitric oxide production. Inhibition of Erk1/2 phosphorylation induced the expression of Ifn-β mRNA, and IFN-β promoted nitric oxide production in microglia. In the ischemic cortex, the expression of Ifn-β mRNA was downregulated by Sema4D deficiency. These findings indicated that the enhancement of nitric oxide production by Sema4D is involved in partial Erk1/2 inhibition and upregulation of IFN-β.

Keywords: Erk1/2; IFN-β; Microglia; NO; Sema4D.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD / metabolism
Antigens, Differentiation, B-Lymphocyte / metabolism
Brain Ischemia / metabolism
Cells, Cultured
Flavonoids / pharmacology
Interferon-beta / genetics
Interferon-beta / metabolism*
Lipopolysaccharides / pharmacology
Mice, Inbred C57BL
Mice, Knockout
Microglia / drug effects
Microglia / metabolism*
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 1 / metabolism*
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 / metabolism*
Nerve Tissue Proteins / metabolism
Nitric Oxide / metabolism*
Phosphorylation
Receptors, Cell Surface / metabolism
Semaphorins / genetics
Semaphorins / metabolism*
Up-Regulation

Substances

Antigens, CD
Antigens, Differentiation, B-Lymphocyte
CD72 antigen, mouse
Flavonoids
Lipopolysaccharides
Nerve Tissue Proteins
Plxnb1 protein, mouse
Receptors, Cell Surface
Sema4d protein, mouse
Semaphorins
Nitric Oxide
Interferon-beta
Mapk1 protein, mouse
Mapk3 protein, mouse
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one