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

4 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

Fingerprint

Microglia
Encephalitis
Proteins
Lipopolysaccharides
Protein Deficiency
Chemokine CCL2
Tumor Necrosis Factor-alpha
Phosphorylation
MAP Kinase Kinase 4
Intraventricular Injections
Macrophage Activation
JNK Mitogen-Activated Protein Kinases
Kainic Acid
Mitogen-Activated Protein Kinase Kinases
Brain
p38 Mitogen-Activated Protein Kinases
Mitogens
Dinoprostone
Neurodegenerative Diseases
Cell Death

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Fujikawa, R., Higuchi, S., Nakatsuji, M., Yasui, M., Ikedo, T., Nagata, 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

EP4 Receptor-Associated Protein in Microglia Promotes Inflammation in the Brain. / Fujikawa, Risako; Higuchi, Sei; Nakatsuji, Masato; Yasui, Mika; Ikedo, Taichi; Nagata, Manabu; Yokode, Masayuki; Minami, Manabu.

In: American Journal of Pathology, Vol. 186, No. 8, 01.08.2016, p. 1982-1988.

Research output: Contribution to journalArticle

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, vol. 186, no. 8, pp. 1982-1988. https://doi.org/10.1016/j.ajpath.2016.04.002
Fujikawa, Risako ; Higuchi, Sei ; Nakatsuji, Masato ; Yasui, Mika ; Ikedo, Taichi ; Nagata, Manabu ; Yokode, Masayuki ; Minami, Manabu. / EP4 Receptor-Associated Protein in Microglia Promotes Inflammation in the Brain. In: American Journal of Pathology. 2016 ; Vol. 186, No. 8. pp. 1982-1988.
@article{bb4613a863214fd7a248d72a2cd95fe4,
title = "EP4 Receptor-Associated Protein in Microglia Promotes Inflammation in the Brain",
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.",
author = "Risako Fujikawa and Sei Higuchi and Masato Nakatsuji and Mika Yasui and Taichi Ikedo and Manabu Nagata and Masayuki Yokode and Manabu Minami",
year = "2016",
month = "8",
day = "1",
doi = "10.1016/j.ajpath.2016.04.002",
language = "English",
volume = "186",
pages = "1982--1988",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "8",

}

TY - JOUR

T1 - EP4 Receptor-Associated Protein in Microglia Promotes Inflammation in the Brain

AU - Fujikawa, Risako

AU - Higuchi, Sei

AU - Nakatsuji, Masato

AU - Yasui, Mika

AU - Ikedo, Taichi

AU - Nagata, Manabu

AU - Yokode, Masayuki

AU - Minami, Manabu

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84990068241&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84990068241&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2016.04.002

DO - 10.1016/j.ajpath.2016.04.002

M3 - Article

C2 - 27315781

AN - SCOPUS:84990068241

VL - 186

SP - 1982

EP - 1988

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 8

ER -