title: miR-124a and miR-155 enhance differentiation of regulatory T cells in patients with neuropathic pain.
abstract: Accumulating evidence indicates that neuropathic pain is a neuro-immune disorder with enhanced activation of the immune system. Recent data provided proof that neuropathic pain patients exhibit increased numbers of immunosuppressive regulatory T cells (Tregs), which may represent an endogenous attempt to limit inflammation and to reduce pain levels. We here investigate the molecular mechanisms underlying these alterations.
  
  
  
  Our experimental approach includes functional analyses of primary human T cells, 3'-UTR reporter assays, and expression analyses of neuropathic pain patients' samples.
  
  
  
  We demonstrate that microRNAs (miRNAs) are involved in the differentiation of Tregs in neuropathic pain. We identify miR-124a and miR-155 as direct repressors of the histone deacetylase sirtuin1 (SIRT1) in primary human CD4(+) cells. Targeting of SIRT1 by either specific siRNA or by these two miRNAs results in an increase of Foxp3 expression and, consecutively, of anti-inflammatory Tregs (siRNA: 1.7 ± 0.4; miR-124a: 1.5 ± 0.4; miR-155: 1.6 ± 0.4; p < 0.01). As compared to healthy volunteers, neuropathic pain patients exhibited an increased expression of miR-124a (2.5 ± 0.7, p < 0.05) and miR-155 (1.3 ± 0.3; p < 0.05) as well as a reduced expression of SIRT1 (0.5 ± 0.2; p < 0.01). Moreover, the expression of these two miRNAs was inversely correlated with SIRT1 transcript levels.
  
  
  
  Our findings suggest that in neuropathic pain, enhanced targeting of SIRT1 by miR-124a and miR-155 induces a bias of CD4(+) T cell differentiation towards Tregs, thereby limiting pain-evoking inflammation. Deciphering miRNA-target interactions that influence inflammatory pathways in neuropathic pain may contribute to the discovery of new roads towards pain amelioration.
  
  
  
  German Clinical Trial Register DRKS00005954.
authors.affiliation: Department of Anesthesiology, Ludwig-Maximilians University Munich, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Heyn
authors.affiliation: Department of Anesthesiology, Ludwig-Maximilians University Munich, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Luchting
authors.affiliation: Department of Anesthesiology, Ludwig-Maximilians University Munich, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Ludwig C
authors.initials: LC
authors.lastname: Hinske
authors.affiliation: Department of Anesthesiology, Ludwig-Maximilians University Munich, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Hübner
authors.affiliation: Department of Anesthesiology, Ludwig-Maximilians University Munich, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Shahnaz C
authors.initials: SC
authors.lastname: Azad
authors.affiliation: Department of Anesthesiology, Ludwig-Maximilians University Munich, Marchioninistr. 15, 81377, Munich, Germany. Simone.Kreth@med.uni-muenchen.de.
authors.forename: Simone
authors.initials: S
authors.lastname: Kreth
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D016296:Mutagenesis / Q000235:genetics; D009437:Neuralgia / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D014162:Transfection
chemical_list: D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C509207:MIRN124 microRNA, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Analgesia; Histone deacetylase sirtuin1; Neuropathic pain; Regulatory T cells; miRNA