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

Takahiro Masuda1, Shosuke Iwamoto2, Ryohei Yoshinaga2

  • 11] 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.

Nature Communications
|May 14, 2014
PubMed

Insights

Interferon regulatory factor-5 (IRF5) drives neuropathic pain by controlling P2X4R expression in spinal microglia after nerve injury. IRF5, regulated by IRF8, offers a potential therapeutic target for pain relief.

Area of Science:

  • Neuroscience
  • Immunology
  • Molecular Biology

Background:

  • Microglia, the immune cells of the central nervous system, adopt reactive phenotypes in response to neuronal injury.
  • Spinal microglia expressing the P2X4 receptor (P2X4R) are linked to neuropathic pain following peripheral nerve injury (PNI).

Purpose of the Study:

  • To investigate the role of interferon regulatory factor-5 (IRF5) in the transcriptional control of P2X4R in spinal microglia after PNI.
  • To elucidate the regulatory pathway involving IRF8 and IRF5 in microglial activation and neuropathic pain.

Main Methods:

  • Analysis of gene expression in spinal microglia following PNI.
  • Investigation of IRF5 binding to the P2rx4 gene promoter.
  • Assessment of neuropathic pain phenotypes in wild-type and Irf5-deficient mice.

Main Results:

  • IRF5 is induced in spinal microglia after PNI and directly controls P2X4R expression.
  • IRF5 binds to the P2rx4 gene promoter, inducing de novo P2X4R expression upon microglial stimulation.
  • Mice lacking Irf5 show reduced P2X4R upregulation and resistance to pain hypersensitivity after PNI.
  • IRF5 expression in microglia is regulated by IRF8.

Conclusions:

  • An IRF8-IRF5 transcriptional axis regulates the shift of spinal microglia to a P2X4R-expressing reactive state post-PNI.
  • Targeting the IRF8-IRF5-P2X4R pathway presents a potential strategy for treating neuropathic pain.

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