Th224 - Sex-specific Unconventional Neutrophils Determine Immunological Outcome in Autoinflammatory Disease

Abstract Text: Neutrophils are the most abundant immune cell type that first responds to immune insults in circulation. Although associative evidence suggests that sex differences in neutrophil may be linked to the sex-specific incidence of inflammatory diseases, mechanistic links remain elusive. Here, we identified extensive sex-specific heterogeneity in neutrophil composition under normal and inflammatory conditions at single-cell resolution. Using a combination of single-cell RNA sequencing analysis, neutrophil-specific genetic knockouts and transfer experiments, we found that dysregulated unconventional (interferon-responsive/T cell regulatory) neutrophil subsets led to higher incidence and severity of autoinflammatory Behçet's disease (BD) in males. In addition, male-specific negative effects of both genetic factors and circulating exosomes on interferon-α responsive neutrophil subset that also contributed to vulnerability to disease in males. IFN-α2a, an FDA-approved immune- regulatory agent, also exerts its immunomodulatory effects by promoting interferon-α responsive neutrophil subset more immune-regulatory phenotype. These findings identify sex-specifically distinct neutrophil subsets with different functionalities, and highlight unconventional neutrophil subsets as therapeutic targets for effective prevention and treatment of inflammatory diseases.