CE15 - Immunologie, Infectiologie et Inflammation

Soluble CD95L in neutrophil homeostasis in ANCA-associated vasculitis – FASAAV

Submission summary

CD95 is a death receptor that belongs to the TNF receptor family. Its cognate ligand CD95L (also known as FasL) is a member of the TNF family. CD95L is a transmembrane protein that interacts with CD95 and can be cleaved by metalloproteases to release a soluble ligand (sCD95L). This cytokine promotes inflammation in lupus via the induction of a Ca2+ response in Th17 cells. We developed a selective inhibitor of this Ca2+ signal designated DB550 (Nat Chem Biol, 2018). Neutrophils produce ROS, which are involved in phagocytosis, degranulation, secretion of inflammatory cytokines and the release of neutrophil extracellular traps (NETs) to fight pathogens. These cellular processes are also implicated in auto-immunity and contribute to vasculitis in anti-neutrophil cytoplasm antibodies associated vasculitis (AAV) patients. AAV is an autoimmune disease affecting blood vessels. We observed that CD95L is over-expressed by endothelial cells in inflammed organs of AAV patients. This protein seems to be cleaved by metalloprotease to release sCD95L, which is accumulated in AAV patients in whom it induces robust ROS and Ca2+ responses in neutrophils. We establish that DB550 treatment alleviates clinical symptoms in AAV mice suggesting that sCD95L could participate in the severity of AAV by deregulating neutrophil homeostasis. This proposal aims at i) undertsanding the biological role of sCD95L in AAV patients, ii) deciphering the molecular mechanism induced by s-CD95L in AAV neutrophils and iii) identifying new therapeutic drugs abrogating the sCD95L-mediated pro-inflammatory signal in AAV neutrophils.

Project coordinator

Monsieur Patrick Blanco (Immunologie Conceptuelle, Expérimentale et Translationnelle)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM UMR1262 CRIBL INSERM UMR1262 - Contrôle des réponses immunes B et lymphoproliférations
ImmunoConcEpT Immunologie Conceptuelle, Expérimentale et Translationnelle
CRCTB CENTRE DE RECHERCHE CARDIO-THORACIQUE DE BORDEAUX

Help of the ANR 665,471 euros
Beginning and duration of the scientific project: October 2022 - 36 Months

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