miR-124a and miR-155 enhance differentiation of regulatory T cells in patients with neuropathic pain

Background: 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. Methods: Our experimental approach includes functional analyses of primary human T cells, 3'-UTR reporter assays, and expression analyses of neuropathic pain patients' samples. Results: 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 miR124a (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. Conclusions: 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