Abstract
BackgroundAccumulating 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.MethodsOur experimental approach includes functional analyses of primary human T cells, 3′-UTR reporter assays, and expression analyses of neuropathic pain patients’ samples.ResultsWe 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.ConclusionsOur 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.Trial registrationGerman Clinical Trial Register DRKS00005954Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0712-6) contains supplementary material, which is available to authorized users.
Highlights
Accumulating evidence indicates that neuropathic pain is a neuro-immune disorder with enhanced activation of the immune system
We focused on the expression of the histone deacetylase sirtuin1 (SIRT1), which is supposed to play a significant role in the development and function of Regulatory T cells (Tregs) [11, 12]
SIRT1 messenger RNA (mRNA) expression is decreased in neuropathic pain First, to confirm our previous findings, we determined the Foxp3/CD4+ cell ratio in neuropathic pain patients as compared to healthy volunteers
Summary
Accumulating evidence indicates that neuropathic pain is a neuro-immune disorder with enhanced activation of the immune system. Neuropathic pain is caused by impairment of somatosensory functions in both the peripheral and central nervous system [1]. It is often associated with spontaneous pain, dysesthesia, paraesthesia, and hyperalgesia (increased pain caused by painful stimuli) and allodynia (increased pain caused by non-painful stimuli) [2, 3]. There is emerging evidence that aberrant responses of the immune system substantially contribute to the development of neuropathic pain [6]. Recent data investigating neuropathic pain in humans published by
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