title: Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain.
abstract: In response to neuronal injury or disease, microglia adopt distinct reactive phenotypes via the expression of different sets of genes. Spinal microglia expressing the purinergic P2X4 receptor (P2X4R) after peripheral nerve injury (PNI) are implicated in neuropathic pain. Here we show that interferon regulatory factor-5 (IRF5), which is induced in spinal microglia after PNI, is responsible for direct transcriptional control of P2X4R. Upon stimulation of microglia by fibronectin, IRF5 induced de novo expression of P2X4R by directly binding to the promoter region of the P2rx4 gene. Mice lacking Irf5 did not upregulate spinal P2X4R after PNI, and also exhibited substantial resistance to pain hypersensitivity. Furthermore, we found that expression of IRF5 in microglia is regulated by IRF8. Thus, an IRF8-IRF5 transcriptional axis may contribute to shifting spinal microglia toward a P2X4R-expressing reactive state after PNI. These results may provide a new target for treating neuropathic pain.
authors.affiliation: 1] Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan [2] Core Research for Evolution Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Shosuke
authors.initials: S
authors.lastname: Iwamoto
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Yoshinaga
authors.affiliation: 1] Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan [2] Core Research for Evolution Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tozaki-Saitoh
authors.affiliation: Department of Immunology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, 620 University Avenue, Toronto, Ontario, Canada M5G 2C1.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Department of Immunology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: 1] Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan [2] Core Research for Evolution Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D050835:Interferon Regulatory Factors / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D009437:Neuralgia / Q000235:genetics* / Q000378:metabolism; D059348:Peripheral Nerve Injuries / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism*; D058848:Receptors, Purinergic P2X4 / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D012333:RNA, Messenger; D058848:Receptors, Purinergic P2X4; D000099185:Interferon Regulatory Factor-8; C498178:Irf5 protein, mouse