2. Academic Validation
  3. Podocyte SIRPα reduction aggravates lupus nephritis via promoting T cell inflammatory responses

Podocyte SIRPα reduction aggravates lupus nephritis via promoting T cell inflammatory responses

  • Cell Rep. 2024 May 28;43(5):114249. doi: 10.1016/j.celrep.2024.114249.
Bin Qian 1,  Rui Lu 1,  Shuya Mao 1,  Yang Chen 1,  Miao Yang 1,  Wenxuan Zhang 2,  Mingchao Zhang 3,  Dihan Zhu 1,  Zhihong Liu 3,  Ke Zen 4,  Limin Li 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
  • 2 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
  • 3 National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China.
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China. Electronic address: kzen@nju.edu.cn.
  • 5 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China. Electronic address: liminli@cpu.edu.cn.
PMID: 38758648 DOI: 10.1016/j.celrep.2024.114249
Abstract

Signal-regulatory protein alpha (SIRPα) has recently been found to be highly expressed in podocytes and is essential for maintaining podocyte function. However, its immunoregulatory function in podocytes remains elusive. Here, we report that SIRPα controls podocyte antigen presentation in specific T cell activation via inhibiting spleen tyrosine kinase (Syk) phosphorylation. First, podocyte SIRPα under lupus nephritis (LN) conditions is strongly downregulated. Second, podocyte-specific deletion of SIRPα exacerbates renal disease progression in lupus-prone mice, as evidenced by an increase in T cell infiltration. Third, SIRPα deletion or knockdown enhances podocyte antigen presentation, which activates specific T cells, via enhancing Syk phosphorylation. Supporting this, Syk Inhibitor GS-9973 prevents podocyte antigen presentation, resulting in a decrease of T cell activation and mitigation of renal disease caused by SIRPα knockdown or deletion. Our findings reveal an immunoregulatory role of SIRPα loss in promoting podocyte antigen presentation to activate specific T cell immune responses in LN.

Keywords

CP: Immunology; SIRPα; T cell immune response; antigen presentation; lupus nephritis; podocyte; spleen tyrosine kinase.

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Inhibitors & Agonists
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15968
    99.88%, Syk Inhibitor
    Syk
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