TY - JOUR
T1 - Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain
AU - Masuda, Takahiro
AU - Iwamoto, Shosuke
AU - Yoshinaga, Ryohei
AU - Tozaki-Saitoh, Hidetoshi
AU - Nishiyama, Akira
AU - Mak, Tak W.
AU - Tamura, Tomohiko
AU - Tsuda, Makoto
AU - Inoue, Kazuhide
N1 - Funding Information:
We appreciate the technical support from the Research Support Center, Graduate School of Medical Sciences, Kyushu University.
Funding Information:
We thank Ms Nao Nishimoto for assisting with the experiments, Dr Keiko Ozato for kindly providing Irf8−/− mice and Dr Tadatsugu Taniguchi for kindly providing Irf5−/− mice. We also thank Dr Chie Hotta for assisting with the experiments. This work was supported by grants from the Japan Society for the Promotion of Science (JSPS) through the ‘Funding Program for Next Generation World-Leading Researchers (NEXT Program)’ initiated by the Council for Science and Technology Policy (CSTP) (M.T.) and the Ministry of Education, Culture, Sports, Science and Technology of Japan (T.M., M.T. and K.I.) and from the Japan Science and Technology Agency (JST) through the Core Research for Evolutional Science and Technology (CREST) program (K.I.), and was also supported by Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
PY - 2014/5/13
Y1 - 2014/5/13
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms4771
DO - 10.1038/ncomms4771
M3 - Article
C2 - 24818655
AN - SCOPUS:84900460785
SN - 2041-1723
VL - 5
JO - Nature Communications
JF - Nature Communications
M1 - 3771
ER -