MicroRNA-146a-5p attenuates neuropathic pain via suppressing TRAF6 signaling in the spinal cord |
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| Affiliation: | 1. Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Jiangsu 226019, China;2. Department of Nutrition, School of Public Health, Nantong University, Jiangsu 226019, China;3. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China;1. Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China;2. Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226019, China;3. Pain Research Laboratory, Institute of Nautical Medicine, Nantong University, Nantong, Jiangsu 226019, China;4. Department of Occupational Medicine and Environmental Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226019, China;1. Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China;2. Department of Rehabilitation Medicine, Shanghai Shangti Orthopaedic Hospital, Shanghai, China;3. The Second School of Clinical Medical, Xuzhou Medical University, Xuzhou, Jiangsu, China;1. Department of Anesthesiology, The Affiliated Huai’an NO.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, China;2. Department of Orthopedics, The Affiliated Huai’an NO.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, China;1. Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy;2. Center of Clinical Pathology and Innovative Therapy, IRCCS INRCA, Ancona, Italy;3. IRCCS MultiMedica, Milano, Italy;4. Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy;1. Department of Anatomy, School of Basic Medical Sciences, Zhengzhou University, 45001, Zhengzhou, Henan, China;2. Neuroscience Research Institute, School of Basic Medical Sciences, Zhengzhou University, 45001, Zhengzhou, Henan, China;3. Department of Anatomy, Luohe Medical College, 462000, Luohe, Henan, China;4. Department of Anatomy, The Fourth Military Medical University, 710000, Xi''an, Shaan Xi, China |
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| Abstract: | Glia-mediated neuroinflammation plays an important role in the pathogenesis of neuropathic pain. Our recent study demonstrated that TNF receptor associated factor-6 (TRAF6) is expressed in spinal astrocytes and contributes to the maintenance of spinal nerve ligation (SNL)-induced neuropathic pain. MicroRNA (miR)-146a is a key regulator of the innate immune response and was shown to target TRAF6 and reduce inflammation. In this study, we found that in cultured astrocytes, TNF-α, IL-1β, or lipopolysaccharide (LPS) induced rapid TRAF6 upregulation and delayed miR-146a-5p upregulation. In addition, miR-146a-5p mimic blocked LPS-induced TRAF6 upregulation, as well as LPS-induced c-Jun N-terminal kinase (JNK) activation and chemokine CCL2 expression in astrocytes. Notably, LPS incubation with astrocytes enhanced the DNA binding activity of AP-1 to the promoters of mir-146a and ccl2. TRAF6 siRNA or JNK inhibitor SP600125 significantly reduced LPS-induced miR-146a-5p increase in astrocytes. In vivo, intrathecal injection of TNF-α or LPS increased spinal TRAF6 expression. Pretreatment with miR-146a-5p mimic alleviated TNF-α- or LPS-induced mechanical allodynia and reduced TRAF6 expression. Finally, SNL induced miR-146a-5p upregulation in the spinal cord at 10 and 21 days. Intrathecal injection of miR-146a-5p mimic attenuated SNL-induced mechanical allodynia and decreased spinal TRAF6 expression. Taken together, the results suggest that (1) miR-146a-5p attenuates neuropathic pain partly through inhibition of TRAF6 and its downstream JNK/CCL2 signaling, (2) miR-146a-5p is increased by the activation of TRAF6/JNK pathway. Hence, miR-146a-5p may be a novel treatment for chronic neuropathic pain. |
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| Keywords: | MiR-146a-5p TRAF6 JNK CCL2 Astrocyte Neuropathic pain |
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