2. Academic Validation
  3. A shedding soluble form of interleukin-17 receptor D exacerbates collagen-induced arthritis through facilitating TNF-α-dependent receptor clustering

A shedding soluble form of interleukin-17 receptor D exacerbates collagen-induced arthritis through facilitating TNF-α-dependent receptor clustering

  • Cell Mol Immunol. 2021 Aug;18(8):1883-1895. doi: 10.1038/s41423-020-00548-w.
Sihan Liu # 1,  Yanxia Fu # 1 2 3,  Kunrong Mei 4,  Yinan Jiang 4,  Xiaojun Sun 1,  Yinyin Wang 1,  Fangli Ren 1,  Congshan Jiang 5,  Liesu Meng 5,  Shemin Lu 5,  Zhihai Qin 6,  Chen Dong 7,  Xinquan Wang 4,  Zhijie Chang 8,  Shigao Yang 9 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, 100084, Beijing, China.
  • 2 The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, 515041, Guangdong, China.
  • 3 Department of Biochemistry and Molecular Biology, Capital Medical University, 100069, Beijing, China.
  • 4 Center for Structural Biology, School of Life Sciences, Ministry of Education Key Laboratory of Protein Science, Tsinghua University, 100084, Beijing, China.
  • 5 Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, Shanxi, China.
  • 6 Key Laboratory of Protein and Peptide Pharmaceuticals, CAS-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
  • 7 Institute for Immunology and School of Medicine, Tsinghua University, 100084, Beijing, China.
  • 8 State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, 100084, Beijing, China. zhijiec@tsinghua.edu.cn.
  • 9 State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, 100084, Beijing, China. yangshigao@ahmu.edu.cn.
  • 10 School of Life Sciences, Anhui Medical University, Hefei, 230032, China. yangshigao@ahmu.edu.cn.
  • # Contributed equally.
PMID: 32963355 DOI: 10.1038/s41423-020-00548-w
Abstract

Rheumatoid arthritis (RA) is exacerbated by TNF-alpha signaling. However, it remains unclear whether TNF-α-activated TNFR1 and TNFR2 are regulated by extracellular factors. Here, we showed that soluble glycosylated interleukin-17 receptor D (sIL-17RD), which was produced by proteolytic cleavage, enhanced TNF-α-induced RA. We revealed that IL-17RD shedding was induced by the proteolytic Enzyme TACE and enhanced by TNF-α expression in macrophages. Intriguingly, sIL-17RD was elevated in the sera of arthritic mice and rats. Recombinant sIL-17RD significantly enhanced the TNF-α-induced proinflammatory response by promoting TNF-α-TNFR-sIL-17RD complex formation and receptor clustering, leading to the accelerated development of collagen-induced arthritis. Our observations revealed that ectodomain shedding of IL-17RD occurred in RA to boost the TNF-α-induced inflammatory response. Targeting sIL-17RD may provide a new strategy for the therapy of RA.

Keywords

Arthritis; Ectodomain shedding; IL-17RD; TACE/ADAM17; TNF-α signaling.

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