Proteomic Analyses Reveal Higher Levels of Neutrophil Activation in Men Than in Women With Systemic Lupus Erythematosus

OBJECTIVE: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that displays a significant gender difference in terms of incidence and severity. However, the underlying mechanisms accounting for sexual dimorphism remain unclear. The aim of this work was to reveal the heterogeneity in the pathogenesis of SLE between male and female patients. METHODS: PBMC were collected from 15 patients with SLE (7 males, 8 females) and 15 age-matched healthy controls (7 males, 8 females) for proteomic analysis. The proteins of interest were validated in independent samples (6 male SLE, 6 female SLE). Biomarkers for neutrophil activation (calprotectin), neutrophil extracellular traps (cell-free DNA and elastase), and reactive oxygen species (glutathione) were measured, using enzyme-linked immunosorbent assay, in plasma obtained from 52 individuals. RESULTS: Enrichment analysis of proteomic data revealed that type I interferon signaling and neutrophil activation networks mapped to both male and female SLE, while male SLE has a higher level of neutrophil activation compared with female SLE. Western blot validated that PGAM1, BST2, and SERPINB10 involved in neutrophil activation are more abundant in male SLE than in female SLE. Moreover, biomarkers of neutrophil activation and reactive oxygen species were increased in male SLE compared with female SLE. CONCLUSION: Type I interferon activation is a common signature in both male and female SLE, while neutrophil activation is more prominent in male SLE compared with female SLE. Our findings define gender heterogeneity in the pathogenesis of SLE and may facilitate the development of gender-specific treatments.