期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 13, 期 600, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abi4994
关键词
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资金
- Fondation pour la Recherche Medicale (FRM)
- Societe Francaise de Rhumatologie (SFR) [935, 1045]
- Centre national de reference maladies auto-immunes et systemiques rares Est/Sud-ouest (RESO)
- CNRS
- IdEx program of the University of Bordeaux
- CLIP program from the cancer research institute
- Agence Nationale de la Recherche (ANR), program Investissements d'Avenir [ANR-11-EQPX-022]
This study identified a P-selectin-dependent pathway in patients with systemic lupus erythematosus (SLE) and validated it as a potential therapeutic avenue. Platelets from SLE patients interacted with Treg cells via the P-selectin/PSGL-1 axis, affecting Treg cell function and suppressing immune responses. Blocking P-selectin in a mouse model of SLE improved disease features, indicating its potential as a therapeutic target.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (Treg) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with Treg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of Treg cells and particularly follicular Treg cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on Treg cells induced a down-regulation of the transforming growth factor-beta axis, altering the phenotype of Treg cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin-dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue.
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