IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain.
Neuropathic pain, a highly debilitating pain condition that commonly occurs after nerve damage, is a reflection of the aberrant excitability of dorsal horn neurons. This pathologically altered neurotransmission requires a communication with spinal microglia activated by nerve injury. However, how normal resting microglia become activated remains unknown. Here we show that in naive animals spinal microglia express a receptor for the cytokine IFN-gamma (IFN-gammaR) in a cell-type-specific manner and that stimulating this receptor converts microglia into activated cells and produces a long-lasting pain hypersensitivity evoked by innocuous stimuli (tactile allodynia, a hallmark symptom of neuropathic pain). Conversely, ablating IFN-gammaR severely impairs nerve injury-evoked microglia activation and tactile allodynia without affecting microglia in the contralateral dorsal horn or basal pain sensitivity. We also find that IFN-gamma-stimulated spinal microglia show up-regulation of Lyn tyrosine kinase and purinergic P2X(4) receptor, crucial events for neuropathic pain, and genetic approaches provide evidence linking these events to IFN-gammaR-dependent microglial and behavioral alterations. These results suggest that IFN-gammaR is a key element in the molecular machinery through which resting spinal microglia transform into an activated state that drives neuropathic pain.
Tsuda
Makoto
M
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
Masuda
Takahiro
T
Kitano
Junko
J
Shimoyama
Hiroshi
H
Tozaki-Saitoh
Hidetoshi
H
Inoue
Kazuhide
K
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D010146:Pain / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017471:Receptors, Interferon / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058848:Receptors, Purinergic P2X4; D015398:Signal Transduction; D013131:Spine / Q000378:metabolism*; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism; D000096743:Interferon gamma Receptor
D016207:Cytokines; D017471:Receptors, Interferon; D018048:Receptors, Purinergic P2; D058848:Receptors, Purinergic P2X4; D019061:src-Family Kinases; D000096743:Interferon gamma Receptor; C548227:P2rx4 protein, mouse; C060902:lyn protein-tyrosine kinase