EP4 Receptor-Associated Protein in Microglia Promotes Inflammation in the Brain.
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.
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; Japan Society for the Promotion of Science, Kyoto, Japan.
Risako
R
Fujikawa
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Sei
S
Higuchi
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Masato
M
Nakatsuji
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Mika
M
Yasui
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Taichi
T
Ikedo
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Manabu
M
Nagata
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Masayuki
M
Yokode
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: mminami@kuhp.kyoto-u.ac.jp.
Manabu
M
Minami
D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004660:Encephalitis / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
D018797:Cell Cycle Proteins; C506176:Fem1a protein, mouse