Distinct CholinomiR Blood Cell Signature as a Potential Modulator of the Cholinergic System in Women with Fibromyalgia Syndrome

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 (Cho-linomiRs). 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 Choli-nomiRs compared to healthy controls and PD patients. qRT-PCR validated miR-182-5p upregula-tion, distinguishing FMS patients from healthy controls. mRNA targets of CholinomiRs bone mor-phogenic protein receptor 2 and interleukin 6 signal transducer were downregulated. Serum ace-tylcholinesterase 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.