1. Academic Validation
  2. NETs-CD44-IL-17A Feedback Loop Drives Th17-Mediated Inflammation in Behçet's Uveitis

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

  • Adv Sci (Weinh). 2025 Feb 27:e2411524. doi: 10.1002/advs.202411524.
Yi Wu 1 Kang Ning 2 3 Zhaohao Huang 1 Binyao Chen 1 Junjie Chen 1 Yingying Wen 4 Jian Bu 5 Han Hong 5 Qiaorong Chen 5 Zhuoqi Zhang 5 Renbing Jia 6 Wenru Su 1 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, China.
  • 2 Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, 510050, China.
  • 3 State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510050, China.
  • 4 Bengbu Medical University, Bengbu, Anhui, 233030, China.
  • 5 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
  • 6 Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
Abstract

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 CD44highCD4+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.

Keywords

Behçet's uveitis; CD44; IL‐17A; neutrophil extracellular traps; positive feedback loops.

Figures
Products