Chronic morphine-induced MicroRNA-124 promotes microglial immunosuppression by modulating P65 and TRAF6

Shuwei Qiu, Yimin Feng, Gene LeSage, Ying Zhang, Charles Stuart, Lei He, Yi Li, Yi Caudle, Ying Peng, Deling Yin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1021-1030
Number of pages10
JournalJournal of Immunology
Volume194
Issue number3
DOIs
StatePublished - Feb 1 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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