EP4 Receptor-Associated Protein in Microglia Promotes Inflammation in the Brain

Risako Fujikawa, Sei Higuchi, Masato Nakatsuji, Mika Yasui, Taichi Ikedo, Manabu Nagata, Masayuki Yokode, Manabu Minami

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Microglial cells play a key role in neuronal damage in neurodegenerative disorders. Overactivated microglia induce detrimental neurotoxic effects through the excess production of proinflammatory cytokines. However, the mechanisms of microglial activation are poorly understood. We focused on prostaglandin E2 type 4 receptor-associated protein (EPRAP), which suppresses macrophage activation. We demonstrated that EPRAP exists in microglia in the brain. Furthermore, EPRAP-deficient mice displayed less microglial accumulation, and intraperitoneal administration of lipopolysaccharide (LPS) led to reduced expression of tumor necrosis factor-α and monocyte chemoattractant protein-1 mRNA in the brains of EPRAP-deficient mice. Consistently, EPRAP-deficient microglia showed a marked decrease in the production of tumor necrosis factor-α and monocyte chemoattractant protein-1 induced by LPS treatment compared with wild-type controls. In addition, EPRAP deficiency decreased microglial activation and neuronal cell death induced by intraventricular injection of kainic acid. EPRAP deficiency impaired the LPS-induced phosphorylation of c-jun N-terminal kinase and p38 mitogen-activated protein kinase in microglia. The phosphorylation levels of mitogen-activated protein kinase kinase 4—which phosphorylates c-jun N-terminal kinase and p38 mitogen-activated protein kinase—were also decreased in EPRAP-deficient microglia after LPS stimulation. Although EPRAP in macrophages plays a role in the attenuation of inflammation, EPRAP promotes proinflammatory activation of microglia through mitogen-activated protein kinase kinase 4-mediated signaling and may be key to the deteriorating neuronal damage brought on by brain inflammation.

Original languageEnglish
Pages (from-to)1982-1988
Number of pages7
JournalAmerican Journal of Pathology
Volume186
Issue number8
DOIs
Publication statusPublished - Aug 1 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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    Fujikawa, R., Higuchi, S., Nakatsuji, M., Yasui, M., Ikedo, T., Nagata, M., Yokode, M., & Minami, M. (2016). EP4 Receptor-Associated Protein in Microglia Promotes Inflammation in the Brain. American Journal of Pathology, 186(8), 1982-1988. https://doi.org/10.1016/j.ajpath.2016.04.002