TLR signaling adaptor protein MyD88 in primary sensory neurons contributes to persistent inflammatory and neuropathic pain and neuroinflammation.
Increasing evidence suggests that neuro-immune and neuro-glial interactions are critically involved in chronic pain sensitization. It is well studied how immune/glial mediators sensitize pain, but how sensory neurons control neuroinflammation remains unclear. We employed Myd88 conditional knockout (CKO) mice, in which Myd88 was deleted in sodium channel subunit Nav1.8-expressing primary sensory neurons, to examine the unique role of neuronal MyD88 in regulating acute and chronic pain, and possible underlying mechanisms. We found that baseline pain and the formalin induced acute inflammatory pain were intact in CKO mice. However, the late phase inflammatory pain following complete Freund's adjuvant injection and the late phase neuropathic pain following chronic constriction injury (CCI), were reduced in CKO mice. CCI induced up-regulation of MyD88 and chemokine C-C motif ligand 2 expression in DRG neurons and macrophage infiltration into DRGs, and microglia activation in spinal dorsal horns in wild-type mice, but all these changes were compromised in CKO mice. Finally, the pain hypersensitivity induced by intraplantar IL-1β was reduced in CKO mice. Our findings suggest that MyD88 in primary sensory neurons plays an active role in regulating IL-1β signaling and neuroinflammation in the peripheral and the central nervous systems, and contributes to the maintenance of persistent pain.
Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.|Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, 27710 USA.
Xing-Jun
XJ
Liu
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, 27710 USA.|Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, 215021, China.
Tong
T
Liu
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, 27710 USA.
Gang
G
Chen
Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
Bing
B
Wang
Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
Xiao-Lu
XL
Yu
Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
Cui
C
Yin
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, 27710 USA.|Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, 27710 USA.
Ru-Rong
RR
Ji
D000818:Animals; D002478:Cells, Cultured; D059350:Chronic Pain / Q000473:pathology*; D005727:Ganglia, Spinal / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009437:Neuralgia / Q000473:pathology*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
C587672:IL1B protein, mouse; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88