VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation

Olivier Kosmider (), Céline Possémé, Marie Templé, Aurélien Corneau, Francesco Carbone, Eugénie Duroyon, Paul Breillat, Twinu-Wilson Chirayath, Bénédicte Oules, Pierre Sohier, Marine Luka, Camille Gobeaux, Estibaliz Lazaro, Roderau Outh, Guillaume Guenno, François Lifermann, Marie Berleur, Melchior Mene, Chloé Friedrich, Cédric Lenormand, Thierry Weitten, Vivien Guillotin, Barbara Burroni, Jeremy Boussier, Lise Willems, Selim Aractingi, Léa Dionet, Pierre-Louis Tharaux, Béatrice Vergier, Pierre Raynaud, Hang-Korng Ea, Mickael Ménager, Darragh Duffy and Benjamin Terrier ()
Additional contact information
Olivier Kosmider: Université de Paris Cité, Institut Cochin, CNRS UMR8104, INSERM U1016
Céline Possémé: Institut Pasteur, Université de Paris Cité, Translational Immunology Unit
Marie Templé: Université de Paris Cité, Institut Cochin, CNRS UMR8104, INSERM U1016
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
Eugénie Duroyon: Université de Paris Cité, Institut Cochin, CNRS UMR8104, INSERM U1016
Paul Breillat: Université de Paris Cité, INSERM, U970, PARCC, F-
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
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
Chloé Friedrich: Université de Paris Cité, Institut Cochin, CNRS UMR8104, INSERM U1016
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
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
Mickael Ménager: Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163
Darragh Duffy: Institut Pasteur, Université de Paris Cité, Translational Immunology Unit
Benjamin Terrier: Université de Paris Cité, INSERM, U970, PARCC, F-

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44811-4

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