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VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation

Author

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  • Olivier Kosmider

    (Université de Paris Cité, Institut Cochin, CNRS UMR8104, INSERM U1016
    Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris Cité, Cochin Hospital)

  • Céline Possémé

    (Institut Pasteur, Université de Paris Cité, Translational Immunology Unit)

  • Marie Templé

    (Université de Paris Cité, Institut Cochin, CNRS UMR8104, INSERM U1016
    Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris Cité, Cochin Hospital)

  • Aurélien Corneau

    (Sorbonne Université, Faculté de Médecine, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS)

  • Francesco Carbone

    (Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163
    Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163)

  • Eugénie Duroyon

    (Université de Paris Cité, Institut Cochin, CNRS UMR8104, INSERM U1016
    Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris Cité, Cochin Hospital)

  • Paul Breillat

    (Université de Paris Cité, INSERM, U970, PARCC, F-
    National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP, APHP-CUP, Hôpital Cochin)

  • Twinu-Wilson Chirayath

    (Université de Paris Cité, INSERM, UMR-S 1132 BIOSCAR)

  • Bénédicte Oules

    (Department of Pathology, AP-HP, APHP-CUP, Hôpital Cochin)

  • Pierre Sohier

    (Department of Pathology, AP-HP, APHP-CUP, Hôpital Cochin)

  • Marine Luka

    (Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163
    Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163)

  • Camille Gobeaux

    (Biochemistry Laboratory, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris Cité, Cochin Hospital)

  • Estibaliz Lazaro

    (Bordeaux University Hospital-Haut-Lévêque)

  • Roderau Outh

    (Centre Hospitalier de Perpignan)

  • Guillaume Guenno

    (Clermont-Ferrand University Hospital)

  • François Lifermann

    (Côte-d’Argent Hospital)

  • Marie Berleur

    (AP-HP, APHP-NUP, Hôpital Bichat)

  • Melchior Mene

    (Université de Paris Cité, Institut Cochin, CNRS UMR8104, INSERM U1016
    Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris Cité, Cochin Hospital)

  • Chloé Friedrich

    (Université de Paris Cité, Institut Cochin, CNRS UMR8104, INSERM U1016
    Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris Cité, Cochin Hospital)

  • Cédric Lenormand

    (Université de Strasbourg, Department of Dermatology, CHRU Strasbourg)

  • Thierry Weitten

    (Centre Hospitalier (CHICAS))

  • Vivien Guillotin

    (Department of Internal Medicine, Bordeaux University Hospital-Saint-André)

  • Barbara Burroni

    (Department of Pathology, AP-HP, APHP-CUP, Hôpital Cochin)

  • Jeremy Boussier

    (Sorbonne University – 47-83 Boulevard de l’Hopital)

  • Lise Willems

    (Université de Paris Cité, Institut Cochin, CNRS UMR8104, INSERM U1016
    Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris Cité, Cochin Hospital)

  • Selim Aractingi

    (Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris Cité, Cochin Hospital)

  • Léa Dionet

    (Université de Paris Cité, INSERM, U970, PARCC, F-)

  • Pierre-Louis Tharaux

    (Université de Paris Cité, INSERM, U970, PARCC, F-)

  • Béatrice Vergier

    (Bordeaux University Hospital-Haut-Lévêque)

  • Pierre Raynaud

    (Centre Hospitalier de Perpignan)

  • Hang-Korng Ea

    (Université de Paris Cité, INSERM, UMR-S 1132 BIOSCAR
    AP- HP, Lariboisière Hospital)

  • Mickael Ménager

    (Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163
    Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163)

  • Darragh Duffy

    (Institut Pasteur, Université de Paris Cité, Translational Immunology Unit)

  • Benjamin Terrier

    (Université de Paris Cité, INSERM, U970, PARCC, F-
    National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP, APHP-CUP, Hôpital Cochin)

Abstract

Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1β and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome.

Suggested Citation

  • Olivier Kosmider & Céline Possémé & Marie Templé & Aurélien Corneau & Francesco Carbone & Eugénie Duroyon & Paul Breillat & Twinu-Wilson Chirayath & Bénédicte Oules & Pierre Sohier & Marine Luka & Cam, 2024. "VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44811-4
    DOI: 10.1038/s41467-024-44811-4
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