SiglecF Expressing Neutrophils Exacerbate Th17-Mediated Autoimmune Neuroinflammation
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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 in vivo and in vitro. 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.
Abstract
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 in vivo and in vitro. 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.