TY - JOUR A1 - Reinhold, Ann Kristin A1 - Krug, Susanne M. A1 - Salvador, Ellaine A1 - Sauer, Reine S. A1 - Karl-Schöller, Franziska A1 - Malcangio, Marzia A1 - Sommer, Claudia A1 - Rittner, Heike L. T1 - MicroRNA-21-5p functions via RECK/MMP9 as a proalgesic regulator of the blood nerve barrier in nerve injury JF - Annals of the New York Academy of Sciences N2 - Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA-21-5p (miR-21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR-21 in neuropathic pain and its impact on the BNB in a human-murine back translational approach. MiR-21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin-1 in both injured and spared nerves. Moreover, the putative miR-21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR-21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR-21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR-21 after nerve injury reversed it. In summary, the data support a novel role for miR-21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9. KW - claudin-1 KW - RECK KW - MMP9 KW - CRPS KW - microRNA KW - neuropathic pain KW - blood nerve barrier Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318226 VL - 1515 IS - 1 SP - 184 EP - 195 ER - TY - JOUR A1 - Erbacher, Christoph A1 - Vaknine, Shani A1 - Moshitzky, Gilli A1 - Lobentanzer, Sebastian A1 - Eisenberg, Lina A1 - Evdokimov, Dimitar A1 - Sommer, Claudia A1 - Greenberg, David S. A1 - Soreq, Hermona A1 - Üçeyler, Nurcan T1 - Distinct CholinomiR blood cell signature as a potential modulator of the cholinergic system in women with fibromyalgia syndrome JF - Cells N2 - Fibromyalgia syndrome (FMS) is a heterogeneous chronic pain syndrome characterized by musculoskeletal pain and other key co-morbidities including fatigue and a depressed mood. FMS involves altered functioning of the central and peripheral nervous system (CNS, PNS) and immune system, but the specific molecular pathophysiology remains unclear. Anti-cholinergic treatment is effective in FMS patient subgroups, and cholinergic signaling is a strong modulator of CNS and PNS immune processes. Therefore, we used whole blood small RNA-sequencing of female FMS patients and healthy controls to profile microRNA regulators of cholinergic transcripts (CholinomiRs). We compared microRNA profiles with those from Parkinson's disease (PD) patients with pain as disease controls. We validated the sequencing results with quantitative real-time PCR (qRT-PCR) and identified cholinergic targets. Further, we measured serum cholinesterase activity in FMS patients and healthy controls. Small RNA-sequencing revealed FMS-specific changes in 19 CholinomiRs compared to healthy controls and PD patients. qRT-PCR validated miR-182-5p upregulation, distinguishing FMS patients from healthy controls. mRNA targets of CholinomiRs bone morphogenic protein receptor 2 and interleukin 6 signal transducer were downregulated. Serum acetylcholinesterase levels and cholinesterase activity in FMS patients were unchanged. Our findings identified an FMS-specific CholinomiR signature in whole blood, modulating immune-related gene expression. KW - fibromyalgia syndrome KW - cholinergic system KW - CholinomiRs KW - microRNA KW - miR-182-5p KW - Parkinson's disease Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270686 SN - 2073-4409 VL - 11 IS - 8 ER -