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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE334369 | GEO | 2026/06/08

REPOSITORIES: GEO

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Project description:Fibromyalgia is a complex disorder whose main symptoms are chronic widespread pain and fatigue, and affects between 0.2 and 6.6% of the world population. Nowadays, there are no molecular biomarkers which could facilitate diagnosis, underlining the extreme necessity of basic research on this chronic disorder. The latest efforts by the researchers have focused on studying problems at the level of central nervous system sensitivity, inflammatory and oxidative disorders, and even imbalances related to the intestinal microbiota. A total of 892 women were initially enrolled in the study. For those fulfilling inclusion criteria, a plasma proteome analysis in blood samples was conducted. Briefly, blood was collected, centrifuged and analyzed by liquid nano-chromatography coupled to tandem mass spectrometry. After the raw data analysis, proteins with statistically significant differential abundance and a fold change over 1.2 (20% increase in fibromyalgia compared with control samples) or under 0.8 (20% decrease in fibromyalgia compared with control samples) in fibromyalgia were selected. For fecal metagenome analysis, fecal samples were collected, homogenized and processed for DNA extraction. Amplicon sequencing of V3–V4 regions from the 16S ribosomal RNA gene was performed using the Illumina MiSeq platform Quality control procedures were implemented using thresholds set at 50,000 reads per sample, Q30 Phred Score and an average trimmed read length of 280bp. The statistical analysis was conducted using R v4.3.2 base packages. After applying exclusion criteria, 242 women (199 patients and 43 age- and environmentally paired healthy individuals) provided plasma and feces samples, as well as properly filled health questionnaires. A total of 30 proteins and 19 taxa were differentially expressed in fibromyalgia patients, and its integration into an algorithm allows to discriminate cases and controls. The multiomic approach for biomarker discovery in this study propose a multifactorial connection between gut microbiota and mitochondria-derived oxidative stress and inflammation. Plasma and fecal multiomics analysis suggest an intricate and multifactorial connection between gut microbiota and mitochondria-derived oxidative stress and inflammation in FM patients, with glyceraldehyde-3-phosphate dehydrogenase and Streptococcus salivarius as leading actors.

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

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