title: TREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain.
abstract: Neuropathic pain afflicts millions of people, and the development of an effective treatment for this intractable pain is an urgent issue. Recent evidence has implicated microglia in neuropathic pain. The present study showed that the DNAX-activating protein of 12 kDa (DAP12) and its associated "triggering receptor expressed on myeloid cells 2" (TREM2) were predominantly expressed by microglia in the dorsal horn after spinal nerve injury, revealing a role for TREM2/DAP12 signaling in neuropathic pain. Nerve injury-induced proinflammatory cytokine expression in microglia and pain behaviors were significantly suppressed in Dap12-deficient mice. Furthermore, intrathecal administration of TREM2 agonistic antibody induced proinflammatory cytokine expression, as well as neuropathic pain, in mice without nerve injury. The agonistic antibody induced proinflammatory responses and neuropathic pain was not observed in Dap12-deficient mice. Together, these results suggest that TREM2/DAP12-mediated signals in microglia exacerbate nerve injury-induced neuropathic pain by inducing proinflammatory cytokine secretion from microglia. Suppression of DAP12-mediated signals could be a therapeutic target for neuropathic pain.
  
  
  
  Recent studies have revealed that activated microglia in the spinal dorsal horn exacerbate neuropathic pain, which has suggested that suppression of microglial activity should be considered as a therapeutic target. However, only a few molecules have been identified as regulators of microglial activity. In this study, we focused on a receptor complex of TREM2 and DAP12, both of which are expressed by microglia and have been implicated in the pathogenesis of Alzheimer's disease, and demonstrated that TREM2/DAP12 signaling promoted proinflammatory responses in microglia and exacerbates neuropathic pain. The present results revealed the functional significance of TREM2/DAP12 signaling in microglial activation after neuronal injury, and could help in the development of treatments for neuropathic pain and neurodegenerative diseases.
authors: Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors: Masaaki
authors: M
authors: Kobayashi
authors: Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.|Core Research for Evolutional Science and Technology of the Japan Science and Technology Agency, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors: Hiroyuki
authors: H
authors: Konishi
authors: Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.|Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, and.
authors: Akira
authors: A
authors: Sayo
authors: Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
authors: Toshiyuki
authors: 0000-0002-4549-7116
authors: T
authors: Takai
authors: Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, kiyama@med.nagoya-u.ac.jp.|Core Research for Evolutional Science and Technology of the Japan Science and Technology Agency, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors: Hiroshi
authors: 0000-0001-5963-046X
authors: H
authors: Kiyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D018836:Inflammation Mediators / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D009437:Neuralgia / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013116:Spinal Cord / Q000276:immunology* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000276:immunology* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; C484963:Tyrobp protein, mouse
keywords: dap12; microglia; pain; trem2