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

Fibromyalgia (FM) is a long-term pain condition of unknown etiology. We investigated transcriptomic responses of FM and healthy control neutrophils to inflammatory stimuli. 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 post-diagnosis in comparison with those who did improve. Further analysis identified NF-κB suppression as a key biological process associated with low grade inflammation and LPS non-responsiveness in FM neutrophils. The clinically used NF-κB activator, bryostatin, alleviated hypersensitivity in mice treated with FM plasma, pointing to controlled inflammation induction through reactivation of the NF-κB pathway as a possible therapeutic target for FM treatment. Our whole blood single-cell RNA sequencing replicated this NF-κB-driven inflammation and revealed that this inflammatory signature is strongly pronounced not only in neutrophils, but across a broad range of immune cells.