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

Area of Science:

• Ophthalmology
• Immunology
• Cell Biology

Background:

• Behçet's uveitis (BU) involves neutrophil hyperactivation and excessive neutrophil extracellular traps (NETs).
• The precise mechanisms linking NETs to BU pathogenesis are not fully understood.
• Neutrophils in experimental autoimmune uveitis (EAU) promote inflammation via NETs.

Purpose of the Study:

• To elucidate the role of NETs in Behçet's uveitis pathogenesis.
• To investigate the interaction between NETs, T helper 17 (Th17) cells, and IL-17A in BU.
• To identify potential therapeutic targets within this pathway.

Main Methods:

• Comparative analysis of NETs release in BU patients versus healthy controls.
• In vivo and in vitro studies using experimental autoimmune uveitis (EAU) models.
• Single-cell RNA sequencing, multiplex immunofluorescence, and cell communication analyses to identify key molecular interactions.

Main Results:

• Neutrophils from BU patients show increased NETs release.
• Clearing NETs ameliorated EAU symptoms and inhibited Th17 cell differentiation.
• Neutralizing IL-17A reduced neutrophil infiltration and NETs formation in EAU.
• CD44 was identified as a crucial mediator in NETs-Th17 cell interactions, with CD44 antagonism reducing Th17 cells and NETs formation.
• A feedback loop was confirmed: NETs upregulate CD44 to induce Th17 differentiation, which then secrete IL-17A, recruiting neutrophils and promoting more NETs.

Conclusions:

• NETs play a significant role in the pathogenesis of Behçet's uveitis.
• The identified NETs-CD44-IL-17A feedback loop is critical for disease progression.
• Targeting this feedback loop presents a promising therapeutic strategy for Behçet's uveitis.