SiglecF Expressing Neutrophils Exacerbate Th17-Mediated Autoimmune Neuroinflammation

Multiple sclerosis is an autoimmune disease characterized by numerous immune cells, including neutrophils, infiltrating the central nervous system. Previous reports point to a complex role for neutrophils in experimental autoimmune encephalomyelitis (EAE), where their heterogeneity remains poorly understood. In this study, we identified a unique population of neutrophils expressing SiglecF in the brain during EAE that can influence T cell activity. These neutrophils produced elevated levels of Th17-polarizing cytokines, including IL-6, IL-1β, IL-23, and TNF-α, both <i>in vivo</i> and <i>in vitro</i>. Consistent with this cytokine profile, co-culturing SiglecF⁺ neutrophils with CD4⁺ T cells promoted Th17 and GM-CSF⁺ pathogenic Th17 differentiation and proliferation while reducing regulatory T cell numbers. Depleting SiglecF⁺ neutrophils with anti-SiglecF Abs reduced the severity of EAE, decreased the Th17 population, and increased the regulatory T cell population in the brain. These findings suggest that SiglecF⁺ neutrophils promote autoimmune neuroinflammation by reinforcing pathogenic autoreactive Th17 cell responses.