TY - JOUR
T1 - IRF8 Is a Critical Transcription Factor for Transforming Microglia into a Reactive Phenotype
AU - Masuda, Takahiro
AU - Tsuda, Makoto
AU - Yoshinaga, Ryohei
AU - Tozaki-Saitoh, Hidetoshi
AU - Ozato, Keiko
AU - Tamura, Tomohiko
AU - Inoue, Kazuhide
N1 - Funding Information:
This work was supported by grants from the JSPS through the NEXT Program initiated by the CSTP (M.T.) and the MEXT of Japan (T.M., M.T., K.I.) and from the Core-to-Core program of JSPS (K.I.). We thank Ms. Junko Kitano, Ms. Yukari Hasegawa, Dr. Shigeo Hasegawa and the Research Support Center (Graduate School of Medical Sciences, Kyushu University) for assisting with experiments, and Dr. Hiroyuki Miyoshi (RIKEN BioResource Center) for providing the lentiviral vector and its packaging plasmids. T.M. designed and performed most of the experiments, analyzed the data, and wrote the manuscript. M.T. conceived the study, supervised the overall project, performed immunohistochemical experiments, and wrote the manuscript. R.Y. assisted with the experiments. H.T.-S. optimized transduction of lentiviral vectors into primary cultured microglia. K.O. and T.T. provided critical materials including Irf8 –/– mice and advice on data interpretation. K.I. supervised the overall project and wrote the manuscript.
PY - 2012/3/19
Y1 - 2012/3/19
N2 - Microglia become activated by multiple types of damage in the nervous system and play essential roles in neuronal pathologies. However, how microglia transform into reactive phenotypes is poorly understood. Here, we identify the transcription factor interferon regulatory factor 8 (IRF8) as a critical regulator of reactive microglia. Within the spinal cord, IRF8 expression was normally low; however, the expression was markedly upregulated in microglia, but not in neurons or astrocytes, after peripheral nerve injury (PNI). IRF8 overexpression in cultured microglia promoted the transcription of genes associated with reactive states; conversely, IRF8 deficiency prevented these gene expressions in the spinal cord following PNI. Furthermore, IRF8-deficient mice were resistant to neuropathic pain, a common sequela of PNI, and transferring IRF8-overexpressing microglia spinally to normal mice produced pain. Therefore, IRF8 may activate a program of gene expression that transforms microglia into a reactive phenotype. Our findings provide a newly observed mechanism for microglial activation.
AB - Microglia become activated by multiple types of damage in the nervous system and play essential roles in neuronal pathologies. However, how microglia transform into reactive phenotypes is poorly understood. Here, we identify the transcription factor interferon regulatory factor 8 (IRF8) as a critical regulator of reactive microglia. Within the spinal cord, IRF8 expression was normally low; however, the expression was markedly upregulated in microglia, but not in neurons or astrocytes, after peripheral nerve injury (PNI). IRF8 overexpression in cultured microglia promoted the transcription of genes associated with reactive states; conversely, IRF8 deficiency prevented these gene expressions in the spinal cord following PNI. Furthermore, IRF8-deficient mice were resistant to neuropathic pain, a common sequela of PNI, and transferring IRF8-overexpressing microglia spinally to normal mice produced pain. Therefore, IRF8 may activate a program of gene expression that transforms microglia into a reactive phenotype. Our findings provide a newly observed mechanism for microglial activation.
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U2 - 10.1016/j.celrep.2012.02.014
DO - 10.1016/j.celrep.2012.02.014
M3 - Article
C2 - 22832225
AN - SCOPUS:84861123981
SN - 2211-1247
VL - 1
SP - 334
EP - 340
JO - Cell Reports
JF - Cell Reports
IS - 4
ER -