Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain

Takahiro Masuda, Shosuke Iwamoto, Ryohei Yoshinaga, Hidetoshi Saitoh, Akira Nishiyama, Tak W. Mak, Tomohiko Tamura, Tsuda Makoto, Kazuhide Inoue

Research output: Contribution to journalArticle

76 Citations (Scopus)

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.

Original languageEnglish
Article number3771
JournalNature communications
Volume5
DOIs
Publication statusPublished - May 13 2014

Fingerprint

Purinergic P2X4 Receptors
Interferon Regulatory Factors
interferon
pain
Microglia
Neuralgia
nerves
Peripheral Nerve Injuries
Transcription Factors
genes
Genes
phenotype
stimulation
mice
Fibronectins
Genetic Promoter Regions
Drive
Hypersensitivity
Up-Regulation
Phenotype

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain. / Masuda, Takahiro; Iwamoto, Shosuke; Yoshinaga, Ryohei; Saitoh, Hidetoshi; Nishiyama, Akira; Mak, Tak W.; Tamura, Tomohiko; Makoto, Tsuda; Inoue, Kazuhide.

In: Nature communications, Vol. 5, 3771, 13.05.2014.

Research output: Contribution to journalArticle

Masuda, Takahiro ; Iwamoto, Shosuke ; Yoshinaga, Ryohei ; Saitoh, Hidetoshi ; Nishiyama, Akira ; Mak, Tak W. ; Tamura, Tomohiko ; Makoto, Tsuda ; Inoue, Kazuhide. / Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain. In: Nature communications. 2014 ; Vol. 5.
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