title: Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain.
abstract: Although microglia have been implicated in nerve injury-induced neuropathic pain, the manner by which injured sensory neurons engage microglia remains unclear. We found that peripheral nerve injury induced de novo expression of colony-stimulating factor 1 (CSF1) in injured sensory neurons. CSF1 was transported to the spinal cord, where it targeted the microglial CSF1 receptor (CSF1R). Cre-mediated sensory neuron deletion of Csf1 completely prevented nerve injury-induced mechanical hypersensitivity and reduced microglial activation and proliferation. In contrast, intrathecal injection of CSF1 induced mechanical hypersensitivity and microglial proliferation. Nerve injury also upregulated CSF1 in motoneurons, where it was required for ventral horn microglial activation and proliferation. Downstream of CSF1R, we found that the microglial membrane adaptor protein DAP12 was required for both nerve injury- and intrathecal CSF1-induced upregulation of pain-related microglial genes and the ensuing pain, but not for microglial proliferation. Thus, both CSF1 and DAP12 are potential targets for the pharmacotherapy of neuropathic pain.
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA.
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Department of Anatomy, University of California San Francisco, San Francisco, California, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Kuhn
authors.affiliation: Department of Anatomy, University of California San Francisco, San Francisco, California, USA.
authors.forename: Xidao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Anatomy, University of California San Francisco, San Francisco, California, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Colquitt
authors.affiliation: Department of Anatomy, University of California San Francisco, San Francisco, California, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Solorzano
authors.affiliation: Department of Anatomy, University of California San Francisco, San Francisco, California, USA.
authors.forename: Smitha
authors.initials: S
authors.lastname: Vaman
authors.affiliation: Department of Anatomy, University of California San Francisco, San Francisco, California, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Guan
authors.affiliation: Department of Anatomy, University of California San Francisco, San Francisco, California, USA.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Evans-Reinsch
authors.affiliation: Department of Anatomy, University of California San Francisco, San Francisco, California, USA.
authors.forename: Joao
authors.initials: J
authors.lastname: Braz
authors.affiliation: Department for Cell and Animal Biology, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Marshall
authors.initials: M
authors.lastname: Devor
authors.affiliation: Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Abboud-Werner
authors.affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA.
authors.forename: Lewis L
authors.identifier: http://orcid.org/0000-0003-1308-3952
authors.initials: LL
authors.lastname: Lanier
authors.affiliation: Department of Anatomy, University of California San Francisco, San Francisco, California, USA.
authors.forename: Stavros
authors.initials: S
authors.lastname: Lomvardas
authors.affiliation: Department of Anatomy, University of California San Francisco, San Francisco, California, USA.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Basbaum
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism*; D009437:Neuralgia / Q000378:metabolism*; D059348:Peripheral Nerve Injuries / Q000378:metabolism*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000604004:Csf1r protein, mouse; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C484963:Tyrobp protein, mouse; D016173:Macrophage Colony-Stimulating Factor