NETs-CD44-IL-17A Feedback Loop Drives Th17-Mediated Inflammation in Behçet's Uveitis

Behçet's uveitis (BU) is a severe ocular manifestation of Behçet's disease, typically accompanied by abnormal neutrophil infiltration and hyperactivation. However, the underlying causes of excessive neutrophil extracellular traps (NETs) production and mechanisms by which NETs contribute to the pathogenesis of BU remain incompletely understood. Neutrophils from BU patients exhibit a higher propensity for NETs release compared to healthy controls. In the experimental autoimmune uveitis (EAU), neutrophils are observed to exert pro-inflammatory effects through NETs. Clearing NETs can inhibit T helper 17 (Th17) cell differentiation and significantly alleviate EAU symptoms. In vivo and in vitro experiments demonstrate neutralizing IL-17A markedly reducing neutrophil infiltration and NETs formation in EAU. Single-cell RNA sequencing confirms that CD44 plays a key role in mediating interactions between NETs and Th17 cells. Antagonizing CD44 inhibits the proportion of Th17 cells and NETs formation. Multiplex immunofluorescence and cell communication analyses further demonstrate interactions and colocalization between NETs and CD44^highCD4⁺T cells in EAU. NETs induce Th17 differentiation via upregulating CD44, and in turn, Th17 cells secrete IL-17A to recruit neutrophils and promote NETs formation. Interrupting NETs-CD44-IL-17A feedback loop may be a potential therapeutic target for BU.