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      Injured sensory neuron-derived CSF1 induces microglia proliferation and DAP12-dependent pain

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          SUMMARY

          Although microglia are implicated in nerve injury-induced neuropathic pain, how injured sensory neurons engage microglia is unclear. Here we demonstrate that peripheral nerve injury induces de novo expression of colony-stimulating factor 1 (CSF1) in injured sensory neurons. The CSF1 is transported to the spinal cord where it targets the microglial CSF1 receptor (CSF1R). Cre-mediated sensory neuron deletion of Csf1 completely prevented nerve injury-induced mechanical hypersensitivity and reduced microglia activation and proliferation. In contrast, intrathecal injection of CSF1 induces mechanical hypersensitivity and microglial proliferation. Nerve injury also upregulated CSF1 in motoneurons, where it is required for ventral horn microglial activation and proliferation. Downstream of CSF1R, we found that the microglial membrane adapter protein DAP12 is required for both nerve injury- and intrathecal CSF1-induced upregulation of pain-related microglial genes and the ensuing pain, but not for microglia proliferation. Thus, both CSF1 and DAP12 are potential targets for the pharmacotherapy of neuropathic pain.

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          Most cited references34

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          The Microglial Sensome Revealed by Direct RNA Sequencing

          Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings by fluorescent dual in-situ hybridization, unbiased proteomic analysis and quantitative PCR. We report here that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we term the “sensome”. With aging, sensome transcripts for endogenous ligand recognition are downregulated, whereas those involved in microbe recognition and host defense are upregulated. In addition, aging is associated with an overall increase in expression of microglial genes involved in neuroprotection.
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            Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.

            Microgliosis is a common response to multiple types of damage in the CNS. However, the origin of the cells involved in this process is still controversial and the relative importance of local expansion versus recruitment of microglia progenitors from the bloodstream is unclear. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of microglia progenitor recruitment from the circulation in denervation or CNS neurodegenerative disease, suggesting that maintenance and local expansion of microglia are solely dependent on the self-renewal of CNS resident cells in these models.
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              P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury.

              Pain after nerve damage is an expression of pathological operation of the nervous system, one hallmark of which is tactile allodynia-pain hypersensitivity evoked by innocuous stimuli. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. Here we report that pharmacological blockade of spinal P2X4 receptors (P2X4Rs), a subtype of ionotropic ATP receptor, reversed tactile allodynia caused by peripheral nerve injury without affecting acute pain behaviours in naive animals. After nerve injury, P2X4R expression increased strikingly in the ipsilateral spinal cord, and P2X4Rs were induced in hyperactive microglia but not in neurons or astrocytes. Intraspinal administration of P2X4R antisense oligodeoxynucleotide decreased the induction of P2X4Rs and suppressed tactile allodynia after nerve injury. Conversely, intraspinal administration of microglia in which P2X4Rs had been induced and stimulated, produced tactile allodynia in naive rats. Taken together, our results demonstrate that activation of P2X4Rs in hyperactive microglia is necessary for tactile allodynia after nerve injury and is sufficient to produce tactile allodynia in normal animals. Thus, blocking P2X4Rs in microglia might be a new therapeutic strategy for pain induced by nerve injury.
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                1097-6256
                1546-1726
                13 November 2015
                07 December 2015
                January 2016
                07 June 2016
                : 19
                : 1
                : 94-101
                Affiliations
                [1 ]Department of Anesthesia and Perioperative Care, University California San Francisco, San Francisco, CA 94143, USA
                [2 ]Department of Anatomy, University California San Francisco, San Francisco, CA 94143, USA
                [3 ]Department for Cell and Animal Biology, Inst. Life Sciences, Hebrew University of Jerusalem, 92904, Israel
                [4 ]Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
                [5 ]Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
                Author notes
                [* ]Correspondence to: Zhonghui Guan ( zhonghui.guan@ 123456ucsf.edu ) and Allan Basbaum ( Allan.Basbaum@ 123456ucsf.edu )
                [6]

                These authors contributed equally

                [7]

                Current address: Department of Physiology, University California San Francisco, San Francisco, CA 94143, USA.

                [8]

                Current address: Master Program in Translational Medicine, UC Berkeley / UCSF, San Francisco, CA 94143, USA.

                [9]

                Current address: Department of Biochemistry and Molecular Biophysics, Mortimer B. Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10025, USA.

                Article
                NIHMS736517
                10.1038/nn.4189
                4703328
                26642091
                441736ee-824e-4680-8994-e563c29b14b0

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                Neurosciences

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