A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity.
The activation of spinal cord glial cells has been implicated in the development of neuropathic pain upon peripheral nerve injury. The molecular mechanisms underlying glial cell activation, however, have not been clearly elucidated. In this study, we found that damaged sensory neurons induce the expression of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and inducible nitric-oxide synthase genes in spinal cord glial cells, which is implicated in the development of neuropathic pain. Studies using primary glial cells isolated from toll-like receptor 2 knock-out mice indicate that damaged sensory neurons activate glial cells via toll-like receptor 2. In addition, behavioral studies using toll-like receptor 2 knock-out mice demonstrate that the expression of toll-like receptor 2 is required for the induction of mechanical allodynia and thermal hyperalgesia due to spinal nerve axotomy. The nerve injury-induced spinal cord microglia and astrocyte activation is reduced in the toll-like receptor 2 knock-out mice. Similarly, the nerve injury-induced pro-inflammatory gene expression in the spinal cord is also reduced in the toll-like receptor 2 knock-out mice. These data demonstrate that toll-like receptor 2 contributes to the nerve injury-induced spinal cord glial cell activation and subsequent pain hypersensitivity.
Kim
Donghoon
D
Program in Molecular and Cellular Neuroscience, Dental Research Institute, BK21, and Department of Oral Physiology, School of Dentistry, Seoul National University, Seoul 110-749, Korea.
Kim
Myung Ah
MA
Cho
Ik-Hyun
IH
Kim
Mi Sun
MS
Lee
Soojin
S
Jo
Eun-Kyeong
EK
Choi
Se-Young
SY
Park
Kyungpyo
K
Kim
Joong Soo
JS
Akira
Shizuo
S
Na
Heung Sik
HS
Oh
Seog Bae
SB
Lee
Sung Joong
SJ
D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010146:Pain / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000378:metabolism*
D016207:Cytokines; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse