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<p>Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a severe autoimmune disease that lacks effective targeted therapies. T cell and neutrophil activation are associated with tissue lesions in ANCA-associated vasculitis responsible for the necrotizing vasculitis of small blood vessels. Although the aberrant release of reactive oxygen species (ROS) by neutrophils contribute to the disruption of the endothelial barrier, the underlying molecular mechanisms of this oxidative burst remain unclear. Here, we observe that blood vessels in the inflamed organs of patients with AAV express CD95L, which is cleaved by metalloproteases to release soluble CD95L (sCD95L). sCD95L stimulates ROS production in AAV neutrophils via a caspase-driven mechanism. Proteomic analysis reveals that the deubiquitinase OTULIN is a caspase substrate in sCD95L-exposed neutrophils. Caspase-10 cleaves OTULIN after its aspartates at positions 31 and 54 to unleash the activity of E3 ligase complex LUBAC and trigger mitochondrion-dependent ROS production in AAV neutrophils. Inhibition of the CD95-mediated non-apoptotic signaling abrogates ROS production in AAV neutrophils and alleviates clinical symptoms in AAV and crescentic glomerulonephritis mouse models, indicating that CD95 and CD95L represent attractive molecular targets for patients with AAV.</p>

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Soluble CD95L triggers Caspase-10-driven reactive oxygen species production in neutrophils and aggravates anti-neutrophil cytoplasmic antibody-vasculitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月20日

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  • Andréa Boizard-Moracchini,
  • Dhouha Msalbi,
  • Sarah Huot-Marchand,
  • Layla Haymour,
  • Eden Lebrault,
  • John Tchen,
  • Titia Jekel,
  • Gaël Galli,
  • Benoît Brilland,
  • Nathalie Mérillon,
  • Coralie Josensi,
  • Clément Lozano,
  • Juliana Mazars,
  • Matthieu Douard,
  • Yannick Danger,
  • Franck Vérité,
  • Thomas Barnetche,
  • Estibaliz Lazaro,
  • Pierre Duffau,
  • Pierre Pfirmann,
  • Aude Magerus-Chatinet,
  • Mickael Jean,
  • Jean-François Augusto,
  • Jean Armengaud,
  • Christophe Richez,
  • Pierre Vacher,
  • Patrick Legembre,
  • Patrick Blanco

摘要

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a severe autoimmune disease that lacks effective targeted therapies. T cell and neutrophil activation are associated with tissue lesions in ANCA-associated vasculitis responsible for the necrotizing vasculitis of small blood vessels. Although the aberrant release of reactive oxygen species (ROS) by neutrophils contribute to the disruption of the endothelial barrier, the underlying molecular mechanisms of this oxidative burst remain unclear. Here, we observe that blood vessels in the inflamed organs of patients with AAV express CD95L, which is cleaved by metalloproteases to release soluble CD95L (sCD95L). sCD95L stimulates ROS production in AAV neutrophils via a caspase-driven mechanism. Proteomic analysis reveals that the deubiquitinase OTULIN is a caspase substrate in sCD95L-exposed neutrophils. Caspase-10 cleaves OTULIN after its aspartates at positions 31 and 54 to unleash the activity of E3 ligase complex LUBAC and trigger mitochondrion-dependent ROS production in AAV neutrophils. Inhibition of the CD95-mediated non-apoptotic signaling abrogates ROS production in AAV neutrophils and alleviates clinical symptoms in AAV and crescentic glomerulonephritis mouse models, indicating that CD95 and CD95L represent attractive molecular targets for patients with AAV.