title: Chronic morphine-induced microRNA-124 promotes microglial immunosuppression by modulating P65 and TRAF6.
abstract: Opioids have been widely applied in clinics as one of the most potent pain relievers for centuries, but their abuse has deleterious physiological effects including immunosuppression. However, the mechanisms are unclear. TLRs and acetylcholine are widely expressed in the immune and nervous systems, and play critical roles in immune responses. In this article, we show that morphine suppresses the innate immunity in microglia and bone marrow-derived macrophages through differential regulation of TLRs and acetylcholinesterase. Either morphine or inhibition of acetylcholine significantly promotes upregulation of microRNA-124 (miR-124) in microglia, bone marrow-derived macrophages, and the mouse brain, where miR-124 mediates morphine inhibition of the innate immunity by directly targeting a subunit of NF-κB p65 and TNFR-associated factor 6 (TRAF6). Furthermore, transcription factors AP-1 and CREB inhibited miR-124, whereas p65 bound directly to promoters of miR-124, thereby enhancing miR-124 transcription. Moreover, acute morphine treatment transiently upregulated the expression of p65 and phospho-p65 in both nucleus and cytoplasm priming the expression of miR-124, whereas long exposure of morphine maintained miR-124 expression, which inhibited p65- and TRAF6-dependent TLR signaling. These data suggest that modulation of miRs is capable of preventing opioid-induced damage to microglia.
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614; and.
authors.forename: Shuwei
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614; and.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614; and.
authors.forename: Gene
authors.initials: G
authors.lastname: LeSage
authors.affiliation: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614; and.
authors.forename: Charles
authors.initials: C
authors.lastname: Stuart
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China;
authors.forename: Lei
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China;
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614; and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Caudle
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; yin@etsu.edu 2353352460@qq.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614; and yin@etsu.edu 2353352460@qq.com.
authors.forename: Deling
authors.initials: D
authors.lastname: Yin
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D020029:Base Pairing; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D056747:Immunomodulation / Q000235:genetics*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D017628:Microglia / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology; D034622:RNA Interference; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics*; D051996:Transcription Factor RelA / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; D048029:TNF Receptor-Associated Factor 6; D051996:Transcription Factor RelA; D009020:Morphine