Exosome microRNA signatures in patients with complex regional pain syndrome undergoing plasma exchange

Abstract

BackgroundTherapeutic plasma exchange (PE) or plasmapheresis is an extracorporeal procedure employed to treat immunological disorders. Exosomes, nanosized vesicles of endosomal origin, mediate intercellular communication by transferring cargo proteins and nucleic acids and regulate many pathophysiological processes. Exosomal miRNAs are potential biomarkers due to their stability and dysregulation in diseases including complex regional pain syndrome (CRPS), a chronic pain disorder with persistent inflammation. A previous study showed that a subset of CRPS patients responded to PE.MethodsAs a proof-of-concept, we investigated the PE-induced exosomal miRNA changes in six CRPS patients. Plasma cytokine levels were measured by HPLC and correlated with miRNA expression. Luciferase assay following co-transfection of HEK293 cells with target 3′UTR constructs and miRNA mimics was used to evaluate miRNA mediated gene regulation of target mRNA. Transient transfection of THP-1 cells with miRNA mimics followed by estimation of target gene and protein expression was used to validate the findings.ResultsComparison of miRNAs in exosomes from the serum of three responders and three poor-responders showed that 17 miRNAs differed significantly before and after therapy. Of these, poor responders had lower exosomal hsa-miR-338-5p. We show that miR-338-5p can bind to the interleukin 6 (IL-6) 3′ untranslated region and can regulate IL-6 mRNA and protein levels in vitro. PE resulted in a significant reduction of IL-6 in CRPS patients.ConclusionsWe propose that lower pretreatment levels of miR-338-5p in poor responders are linked to IL-6 levels and inflammation in CRPS. Our data suggests the feasibility of exploring exosomal miRNAs as a strategy in patient stratification for maximizing therapeutic outcome of PE.Electronic supplementary materialThe online version of this article (10.1186/s12967-019-1833-3) contains supplementary material, which is available to authorized users.

The role of collagen in cancer: from bench to bedside

“…Exosomes are membrane-enclosed structures that facilitate communication between cancer cells and the ECM to influence cancer cell survival, growth, and metastasis and the immune system [101]. Cancer-derived exosomes induce the formation of CAFs in the collagen matrix to promote EMT [102] and increase the secretion of MMP-14 to regulate collagen [103].…”

Exosomes as a new pain biomarker opportunity

“…Therefore, identification of specific cargo’s profile associated to pain states might lead to distinguish a specific pathological state from a healthy state and to use exosomes as biomarkers of the diseases. Human studies on CRPS identified specific miRNAs that could be useful to identify subgroup of patients in order to find personalized therapeutic strategies, 14 for example, low level of miR-338-5p in CRPS patients could identify poor responders to plasmapheresis treatment; it could suggest clinicians to evaluate alternative strategies. 45 Moreover, in IBD patients’ exosomes, an overexpression of annexine-1 during inflammatory process than healthy controls has been found, highlighting its potential role as diagnosis biomarker.…”

“…Exosomes’ involvement in pain processes have been demonstrated by studies on different chronic pain diseases, in particular osteoarthritis (OA), 9 , 10 rheumatoid arthritis (RA), 11 inflammatory bowel diseases (IBDs), 12 neurodegenerative pathologies, 13 and complex regional pain syndrome (CRPS). 14 From some of these studies, exosomes appear to be a possible novel therapeutic strategy, 15 transferring cargo in close and distance target cells. They have been even identified as a promising treatment able to improve painful symptoms with fewer side effects, 15 with potential immunoprotective 16 and anti-inflammatory role.…”

“… 10 Moreover, it has been found that exosomes might represent a tool to distinguish subgroups of patients with higher possibility to benefit from specific treatments. 14 In this narrative review, we provide an overview of exosomes in pain field present in literature. Possible associations between exosomes and painful diseases are discussed.…”

Non-coding RNAs in neuropathic pain

“…The down-regulation of SIRT1 by miRNAs could thus be causally involved in neuropathic pain generation or in the exacerbation of the immune response [51]. Likewise, the increased IL-6 and VEGF expression resulting from decreased activity of miR-338-5p and miR-939, as well as miR-34a and miR-101 targeting Corticotropin releasing hormone receptor 1 (CRHR1) and Karyopherin beta 1 (KPNB1) are relevant candidates for the inflammatory component of neuropathic pain disorders [41,52,53].…”