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

Abstract 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-κB suppression as a key biological process associated with low-grade inflammation and LPS non-responsiveness in neutrophils from FM patients. 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 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. Competing Interest Statement LD, MP, LVL and JSM have a patent pending application describing the role of inflammatory response in pain resolution and a licensing agreement with Orthgen company related to this patent pending. The other authors have no conflicts of interest to declare.