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Cited by 557

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

Open access
Guan, Zhonghui, Kuhn, Julia A, Wang, Xidao, Colquitt, Bradley, Solorzano, Carlos, Vaman, Smitha, Guan, Andrew K, Evans-Reinsch, Zoe, Braz, Joao, Devor, Marshall, Abboud-Werner, Sherry L, Lanier, Lewis L, Lomvardas, Stavros, Basbaum, Allan I·2016·Nature Neuroscience
DOI 10.1038/nn.4189
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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.

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  1. von Hehn, C.A., Baron, R. & Woolf, C.J. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 73, 638–652 (2012). · DOI · Paper page
  2. Backonja, M. & Woolf, C.J. Future directions in neuropathic pain therapy: closing the translational loop. Oncologist 15 (suppl. 2), 24–29 (2010). · doi:10.1634/theoncologist.2009-s502
  3. Salter, M.W. & Beggs, S. Sublime microglia: expanding roles for the guardians of the CNS. Cell 158, 15–24 (2014). · DOI · Paper page
  4. Beggs, S., Trang, T. & Salter, M.W. P2X4R+ microglia drive neuropathic pain. Nat. Neurosci. 15, 1068–1073 (2012). · DOI · Paper page
  5. Ji, R.R., Berta, T. & Nedergaard, M. Glia and pain: is chronic pain a gliopathy? Pain 154 (suppl. 1), S10–S28 (2013).
  6. Clark, A.K. & Malcangio, M. Fractalkine/CX3CR1 signaling during neuropathic pain. Front. Cell. Neurosci. 8, 121 (2014). · DOI · Paper page
  7. Grace, P.M., Hutchinson, M.R., Maier, S.F. & Watkins, L.R. Pathological pain and the neuroimmune interface. Nat. Rev. Immunol. 14, 217–231 (2014). · DOI · Paper page
  8. Colburn, R.W., Rickman, A.J. & DeLeo, J.A. The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp. Neurol. 157, 289–304 (1999). · DOI · Paper page
  9. Old, E.A. & Malcangio, M. Chemokine mediated neuron-glia communication and aberrant signaling in neuropathic pain states. Curr. Opin. Pharmacol. 12, 67–73 (2012). · DOI
  10. Biber, K. et al. Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. EMBO J. 30, 1864–1873 (2011). · DOI · Paper page
  11. Jung, H. et al. Visualization of chemokine receptor activation in transgenic mice reveals peripheral activation of CCR2 receptors in states of neuropathic pain. J. Neurosci. 29, 8051–8062 (2009). · DOI
  12. Calvo, M. et al. Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury. J. Neurosci. 30, 5437–5450 (2010). · DOI · Paper page
  13. Tsuda, M. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783 (2003). · DOI · Paper page
  14. Ulmann, L. et al. Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J. Neurosci. 28, 11263–11268 (2008). · DOI · Paper page
  15. Priller, J. et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat. Med. 7, 1356–1361 (2001). · DOI · Paper page
  16. Ajami, B., Bennett, J.L., Krieger, C., Tetzlaff, W. & Rossi, F.M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007). · DOI · Paper page
  17. LaCroix-Fralish, M.L., Austin, J.S., Zheng, F.Y., Levitin, D.J. & Mogil, J.S. Patterns of pain: meta-analysis of microarray studies of pain. Pain 152, 1888–1898 (2011). · DOI · Paper page
  18. Perkins, J.R. et al. A comparison of RNA-seq and exon arrays for whole genome transcription profiling of the L5 spinal nerve transection model of neuropathic pain in the rat. Mol. Pain 10, 7 (2014). · DOI
  19. Suzumura, A., Sawada, M., Yamamoto, H. & Marunouchi, T. Effects of colony stimulating factors on isolated microglia in vitro. J. Neuroimmunol. 30, 111–120 (1990). · DOI · Paper page
  20. Tsujino, H. et al. Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: a novel neuronal marker of nerve injury. Mol. Cell. Neurosci. 15, 170–182 (2000). · DOI · Paper page
  21. Hökfelt, T., Brumovsky, P., Shi, T., Pedrazzini, T. & Villar, M. NPY and pain as seen from the histochemical side. Peptides 28, 365–372 (2007). · DOI
  22. Harris, S.E. et al. Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects. Bone 50, 42–53 (2012). · DOI · Paper page
  23. Zurborg, S. et al. Generation and characterization of an Advillin-Cre driver mouse line. Mol. Pain 7, 66 (2011). · DOI
  24. Shields, S.D., Eckert, W.A. III & Basbaum, A.I. Spared nerve injury model of neuropathic pain in the mouse: a behavioral and anatomic analysis. J. Pain 4, 465–470 (2003). · DOI · Paper page
  25. Hickman, S.E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013). · DOI · Paper page
  26. Kobayashi, M., Konishi, H., Takai, T. & Kiyama, H. A DAP12-dependent signal promotes pro-inflammatory polarization in microglia following nerve injury and exacerbates degeneration of injured neurons. Glia 63, 1073–1082 (2015). · DOI
  27. Bakker, A.B. et al. DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming. Immunity 13, 345–353 (2000). · DOI · Paper page
  28. Devor, M. & Raber, P. Heritability of symptoms in an experimental model of neuropathic pain. Pain 42, 51–67 (1990). · DOI · Paper page
  29. Bédard, A., Tremblay, P., Chernomoretz, A. & Vallières, L. Identification of genes preferentially expressed by microglia and upregulated during cuprizone-induced inflammation. Glia 55, 777–789 (2007). · DOI
  30. Otero, K. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin. Nat. Immunol. 10, 734–743 (2009). · DOI · Paper page
  31. Raivich, G. et al. Regulation of MCSF receptors on microglia in the normal and injured mouse central nervous system: a quantitative immunofluorescence study using confocal laser microscopy. J. Comp. Neurol. 395, 342–358 (1998). · DOI
  32. Yamamoto, S., Nakajima, K. & Kohsaka, S. Macrophage-colony stimulating factor as an inducer of microglial proliferation in axotomized rat facial nucleus. J. Neurochem. 115, 1057–1067 (2010). · DOI
  33. Dubois, N.C., Hofmann, D., Kaloulis, K., Bishop, J.M. & Trumpp, A. Nestin-Cre transgenic mouse line Nes-Cre1 mediates highly efficient Cre/loxP mediated recombination in the nervous system, kidney, and somite-derived tissues. Genesis 44, 355–360 (2006). · DOI · Paper page
  34. Raivich, G., Moreno-Flores, M.T., Möller, J.C. & Kreutzberg, G.W. Inhibition of posttraumatic microglial proliferation in a genetic model of macrophage colony-stimulating factor deficiency in the mouse. Eur. J. Neurosci. 6, 1615–1618 (1994). · DOI · Paper page
  35. Biber, K. & Boddeke, E. Neuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain. Front. Cell. Neurosci. 8, 210 (2014). · DOI
  36. Masuda, T. et al. IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype. Cell Reports 1, 334–340 (2012). · DOI · Paper page
  37. Masuda, T. et al. Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain. Nat. Commun. 5, 3771 (2014). · DOI · Paper page
  38. Coull, J.A. et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424, 938–942 (2003). · DOI · Paper page
  39. Sim, J.A. et al. Altered hippocampal synaptic potentiation in P2X4 knock-out mice. J. Neurosci. 26, 9006–9009 (2006). · DOI · Paper page
  40. Cavanaugh, D.J. et al. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc. Natl. Acad. Sci. USA 106, 9075–9080 (2009). · DOI · Paper page
  41. Bráz, J.M. et al. Forebrain GABAergic neuron precursors integrate into adult spinal cord and reduce injury-induced neuropathic pain. Neuron 74, 663–675 (2012). · DOI · Paper page
  42. Wang, X. et al. Excitatory superficial dorsal horn interneurons are functionally heterogeneous and required for the full behavioral expression of pain and itch. Neuron 78, 312–324 (2013). · DOI
  43. Solorzano, C. et al. Primary afferent and spinal cord expression of gastrin-releasing peptide: message, protein, and antibody concerns. J. Neurosci. 35, 648–657 (2015). · DOI

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Metadata

Authors
Guan, Z., Kuhn, J. A., Wang, X., Colquitt, B., Solorzano, C., Vaman, S., Guan, A. K., Evans-Reinsch, Z., Braz, J., Devor, M., Abboud-Werner, S. L., Lanier, L. L., Lomvardas, S., & Basbaum, A. I.
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2015-12-07
Volume
19
Issue
1
Pages
94-101
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.4189
OpenAlex
W2190814680
Cited by
557
References
12
FWCI
24.96
Type
journal article
Language
en
Open access
green
Licence
www.springer.com/tdm (tdm)

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CoChat. (2026). Citation check: Injured sensory neuron–derived CSF1 induces microglial proliferation and DAP12-dependent pain. https://app.cochat.ai/papers/10.1038/nn.4189
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Guan, Z., Kuhn, J. A., Wang, X., Colquitt, B., Solorzano, C., Vaman, S., Guan, A. K., Evans-Reinsch, Z., Braz, J., Devor, M., Abboud-Werner, S. L., Lanier, L. L., Lomvardas, S., & Basbaum, A. I. (2016). Injured sensory neuron–derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nature Neuroscience. https://doi.org/10.1038/nn.4189

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