VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation

Olivier Kosmider (1, 2) , Céline Possémé (3) , Marie Templé (1, 2) , Aurélien Corneau (4) , Francesco Carbone (5) , Eugénie Duroyon (1, 2) , Paul Breillat (6, 2) , Twinu-Wilson Chirayath (7) , Bénédicte Oules (2) , Pierre Sohier (2) , Marine Luka (5) , Camille Gobeaux (2) , Estibaliz Lazaro (8) , Roderau Outh (9) , Guillaume Le Guenno , François Lifermann , Marie Berleur (10) , Melchior Le Mene (1, 2) , Chloé Friedrich (1, 2) , Cédric Lenormand (11) , Thierry Weitten (12) , Vivien Guillotin , Barbara Burroni , Jeremy Boussier (13) , Lise Willems (1) , Selim Aractingi , Léa Dionet (6) , Pierre-Louis Tharaux (6) , Béatrice Vergier , Pierre Raynaud , Hang-Korng Ea (14) , Mickael Ménager (5) , Darragh Duffy (3) , Benjamin Terrier (6, 2)

1 IC UM3 (UMR 8104 / U1016) - Institut Cochin
2 Hôpital Cochin [AP-HP]
3 Immunologie Translationnelle - Translational Immunology lab
4 PASS-CYPS - Cytométrie Pitié-Salpêtrière
5 Equipe Inserm U1163 - Inflammatory Responses and Transcriptomic Networks in diseases
6 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
7 BIOSCAR (UMR_S_1132 / U1132) - Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques
8 Hôpital Haut-Lévêque [CHU Bordeaux]
9 Centre Hospitalier Saint Jean de Perpignan
10 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
11 CHRU Strasbourg
12 Centre Hospitalier de Gap
13 SU - Sorbonne Université
14 Hôpital Lariboisière-Fernand-Widal [APHP]

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.

Domains: Life Sciences [q-bio]; Immunology

Olivier Kosmider, Céline Possémé, Marie Templé, Aurélien Corneau, Francesco Carbone, et al.. VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation. Nature Communications, 2024, 15 (1), pp.910. ⟨10.1038/s41467-024-44811-4⟩. ⟨pasteur-04467897⟩