The potential roles of type I interferon activated neutrophils and neutrophil extracellular traps (NETs) in the pathogenesis of primary Sjögren's syndrome

  • Arthritis Res Ther. 2022 Jul 19;24(1):170. doi: 10.1186/s13075-022-02860-4.
Yu Peng   #  1 ,  Xunyao Wu   #  2 ,  Shulan Zhang   #  1 ,  Chuiwen Deng  1 ,  Lidan Zhao  1 ,  Mu Wang  3 ,  Qingjun Wu  1 ,  Huaxia Yang  1 ,  Jiaxin Zhou  1 ,  Linyi Peng  1 ,  Xuan Luo  1 ,  Yingying Chen  1 ,  Anqi Wang  1 ,  Qiufeng Xiao  1 ,  Wen Zhang  1 ,  Yan Zhao  1 ,  Xiaofeng Zeng  1 ,  Yunyun Fei  4
Affiliations
  • 1. Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China.
  • 2. Clinical Biobank, Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3. Department of Stomatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China.
  • 4. Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China. [email protected].
  • # Contributed equally.
PMID: 35854322 DOI: 10.1186/s13075-022-02860-4
Abstract

Objective: Neutrophils and aberrant NETosis have been implicated in the pathogenesis of diverse autoimmune diseases; however, their roles in primary Sjögren's syndrome (pSS) remain unclear. We aimed to reveal the potential roles of neutrophils and neutrophil extracellular traps (NETs) in pSS.

Methods: pSS patients were enrolled and NETosis markers were measured in plasma and labial glands using ELISA and immunofluorescence. The gene signatures of neutrophils were assessed by RNA-Seq and RT-PCR. Reactive Oxygen Species (ROS), mitochondrial ROS (MitoSOX) production, and JC-1 were measured by flow cytometry.

Results: NETosis markers including cell-free DNA (cf-DNA) and myeloperoxidase (MPO) in plasma and labial glands from pSS patients were significantly higher than healthy controls (HCs) and were associated with disease activity. RNA Sequencing and RT-qPCR revealed activated type I IFN signaling pathway and higher expression of genes related to type I interferon in pSS neutrophils. Further stimulating with IFN-α 2a in vitro significantly induced ROS production and JC-1 monomer percentage in pSS neutrophils.

Conclusions: Our data suggest the involvement of neutrophils and enhanced NETosis in pSS patients. Further mechanism study in vitro revealed that type I IFN activation in pSS neutrophils led to mitochondrial damage and related ROS production which finally result in the generation of NETs.

Keywords
Mitochondrial damage; Neutrophil extracellular traps; Neutrophils; Primary Sjögren’s syndrome; Type I interferon.
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