title: Spinal Microgliosis Due to Resident Microglial Proliferation Is Required for Pain Hypersensitivity after Peripheral Nerve Injury.
abstract: Peripheral nerve injury causes neuropathic pain accompanied by remarkable microgliosis in the spinal cord dorsal horn. However, it is still debated whether infiltrated monocytes contribute to injury-induced expansion of the microglial population. Here, we found that spinal microgliosis predominantly results from local proliferation of resident microglia but not from infiltrating monocytes after spinal nerve transection (SNT) by using two genetic mouse models (CCR2(RFP/+):CX3CR1(GFP/+) and CX3CR1(creER/+):R26(tdTomato/+) mice) as well as specific staining of microglia and macrophages. Pharmacological inhibition of SNT-induced microglial proliferation correlated with attenuated neuropathic pain hypersensitivities. Microglial proliferation is partially controlled by purinergic and fractalkine signaling, as CX3CR1(-/-) and P2Y12(-/-) mice show reduced spinal microglial proliferation and neuropathic pain. These results suggest that local microglial proliferation is the sole source of spinal microgliosis, which represents a potential therapeutic target for neuropathic pain management.
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, People's Republic of China; Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Gu
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Jiyun
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Madhuvika
authors.initials: M
authors.lastname: Murugan
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, People's Republic of China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Ukpong B
authors.initials: UB
authors.lastname: Eyo
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Dongming
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Biomedical Sciences, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Emanuel
authors.initials: E
authors.lastname: DiCicco-Bloom
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Wise
authors.initials: W
authors.lastname: Young
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, People's Republic of China. Electronic address: hldong6@hotmail.com.
authors.forename: Hailong
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: lwu@dls.rutgers.edu.
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Wu
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1 / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology*; D054428:Chemokine CX3CL1 / Q000378:metabolism; D004195:Disease Models, Animal; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009437:Neuralgia / Q000378:metabolism / Q000473:pathology*; D010147:Pain Measurement / Q000379:methods; D059348:Peripheral Nerve Injuries / Q000378:metabolism / Q000473:pathology*; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism / Q000473:pathology*; D013127:Spinal Nerves / Q000378:metabolism / Q000473:pathology
chemical_list: D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; C548577:P2ry12 protein, mouse; D058925:Receptors, Purinergic P2Y12