Meloto, C. B. | bioRxiv Science

bioRxiv2025

Paradoxical Phenotype of Fibromyalgia Neutrophils with Elevated Baseline Inflammation but Blunted Response to Stimulation

Fibromyalgia (FM) is a severe pain condition of unknown etiology. Here, we performed transcriptomics analyses of peripheral neutrophils exposed to an inflammatory stimulus, comparing responses of neutrophils obtained from FM patients versus healthy controls. We observed a state of inflammation in neutrophils from FM patients. However, FM neutrophils were unable to efficiently respond to lipopolysaccharide (LPS). This impairment was especially characteristic of FM patients with no improvement after 5 years after diagnosis in comparison with those who did improve. Blood plasma from FM patients directly stimulated a wide range of primary sensory neurons in vitro and induced pain hypersensitivity when injected into mice. Further analysis identified NF-{kappa}B suppression as a key biological process associated with low-grade inflammation and LPS non-responsiveness in neutrophils from FM patients. The clinically used NF-{kappa}B activator, bryostatin, alleviated hypersensitivity in mice treated with FM plasma, pointing to controlled inflammation induction through reactivation of the NF-{kappa}B pathway as a possible therapeutic target for FM treatment. Our whole blood single-cell RNA sequencing replicated this NF-{kappa}B-driven inflammation observed in bulk analyses transcriptomics in FM patients and revealed that this inflammatory signature is strongly pronounced not only in neutrophils, but across a broad range of immune cells.

molecular biology↗

bioRxiv2022

Fibromyalgia patients with high levels of anti-satellite glia cell IgG antibodies present with more severe symptoms

ObjectiveTransferring fibromyalgia patient IgG to mice induces pain-like behaviour and fibromyalgia IgG binds mouse and human satellite glia cells (SGCs). These findings suggest that autoantibodies could be part of fibromyalgia pathology. However, it is unknown how frequently fibromyalgia patients have anti-SGC antibodies and how anti-SGC antibodies associate with disease severity. MethodsWe quantified serum or plasma anti-SGC IgG levels in two fibromyalgia cohorts from Sweden and Canada using an indirect immunofluorescence murine cell culture assay. Fibromyalgia serum IgG binding to human SGCs in human dorsal root ganglia tissue sections was assessed by immunofluorescence (n=14/group). ResultsIn the cell culture assay anti-SGC IgG levels were increased in both fibromyalgia cohorts compared to controls. Elevated anti-SGC IgG was associated with higher levels of self-reported pain in both cohorts, and higher fibromyalgia impact questionnaire scores and increased pressure sensitivity in the Swedish cohort. Anti-SGC IgG levels were not associated with fibromyalgia duration. Swedish FM patients were clustered into FM-severe and FM-mild groups and the FM-severe group had elevated anti-SGC IgG compared to the FM-mild and controls. Anti-SGC IgG levels detected in culture were positively correlated with increased binding to human SGCs. Moreover, the FM-severe group had elevated IgG binding to human SGCs compared to the FM-mild and control groups. ConclusionsA subset of fibromyalgia patients have elevated levels of anti-SGC antibodies, and the antibodies are associated with more severe fibromyalgia severity. Screening fibromyalgia patients for anti-SGC antibodies could provide a path to personalized treatment options that target autoantibodies and autoantibody production.

neuroscience↗