Soluble CD95L triggers Caspase-10-driven reactive oxygen species production in neutrophils and aggravates anti-neutrophil cytoplasmic antibody-vasculitis PMID: 42321206

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2026 Jun 20. doi: 10.1038/s41467-026-74452-8.

Andréa Boizard-Moracchini ^# ¹ ² , Dhouha Msalbi ^# ³ , Sarah Huot-Marchand ^# ¹ ⁴ , Layla Haymour ³ , Eden Lebrault ³ , John Tchen ¹ ⁴ , Titia Jekel ¹ , Gaël Galli ¹ ⁴ , Benoît Brilland ⁵ ⁶ , Nathalie Mérillon ¹ ⁴ ⁶ , Coralie Josensi ¹ , Clément Lozano ⁷ , Juliana Mazars ³ , Matthieu Douard ⁸ , Yannick Danger ⁹ , Franck Vérité ⁹ , Thomas Barnetche ⁴ , Estibaliz Lazaro ⁴ ¹⁰ , Pierre Duffau ¹¹ , Pierre Pfirmann ¹² , Aude Magerus-Chatinet ¹³ , Mickael Jean ¹⁴ , Jean-François Augusto ⁵ ⁶ , Jean Armengaud ⁷ , Christophe Richez ¹ ⁴ ¹⁵ , Pierre Vacher ⁸ , Patrick Legembre ^# ¹⁶ ¹⁷ , Patrick Blanco ^# ¹⁸ ¹⁹ ²⁰

Affiliations

1. University of Bordeaux, CNRS, ImmunoConcEpT, UMR, Bordeaux, France.
2. Department of Immunology and Immunogenetics, Bordeaux University Hospital, Bordeaux, France.
3. INSERM U1262, UMR 7276, CRIBL, University of Limoges, Limoges, France.
4. Centre national de référence maladie auto-immune et systémique rares Est/Sud-Ouest (RESO), Bordeaux University Hospital, Bordeaux, France.
5. Service de Néphrologie-Dialyse-Transplantation, University of Angers, CHU Angers, Angers, France.
6. Univ Angers, Nantes Université, Inserm, CNRS, SFR ICAT, CRCI2NA, Angers, France.
7. University of Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, Bagnols-sur-Cèze, France.
8. University of Bordeaux, INSERM U1045, Centre de Recherche Cardio-Thoracique de Bordeaux, Pessac, France.
9. EFS Rennes, Rue Pierre Jean Gineste, Rennes, Cedex, France.
10. Internal Medicine Department, Haut-Leveque, Bordeaux University Hospital, Pessac, France.
11. Internal Medicine Department, Saint André, Bordeaux University Hospital, Bordeaux, France.
12. Nephrology Department, Bordeaux University Hospital, Bordeaux, France.
13. INSERM U1163. IMAGINE - Institut des Maladies Génétiques, Paris, France.
14. University of Rennes, CNRS, ISCR - UMR 6226, Rennes, France.
15. Department of Rheumatology, Pellegrin, Bordeaux University Hospital, Bordeaux, France.
16. INSERM U1262, UMR 7276, CRIBL, University of Limoges, Limoges, France. [email protected].
17. CIRI-Centre International de Recherche en Infectiologie, Team GIMAP, Inserm, U1111, CNRS, UMR5308, Université Saint-Etienne, Bordeaux, France. [email protected].
18. University of Bordeaux, CNRS, ImmunoConcEpT, UMR, Bordeaux, France. [email protected].
19. Department of Immunology and Immunogenetics, Bordeaux University Hospital, Bordeaux, France. [email protected].
20. Centre national de référence maladie auto-immune et systémique rares Est/Sud-Ouest (RESO), Bordeaux University Hospital, Bordeaux, France. [email protected].
# Contributed equally.

Abstract

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.