RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation-Reference-Cited by-同舟云学术

RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation

Published:2024-08-30 Issue:10 Volume:221 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Doye Anne¹^ORCID,Chaintreuil Paul¹^ORCID,Lagresle-Peyrou Chantal²³⁴^ORCID,Batistic Ludovic¹^ORCID,Marion Valentine¹^ORCID,Munro Patrick¹^ORCID,Loubatier Celine¹^ORCID,Chirara Rayana¹⁵^ORCID,Sorel Nataël³⁴^ORCID,Bessot Boris³⁴^ORCID,Bronnec Pauline⁶⁷^ORCID,Contenti Julie¹⁵^ORCID,Courjon Johan¹⁵^ORCID,Giordanengo Valerie¹⁵^ORCID,Jacquel Arnaud¹^ORCID,Barbry Pascal⁸^ORCID,Couralet Marie⁸^ORCID,Aladjidi Nathalie⁹^ORCID,Fischer Alain³¹⁰¹¹^ORCID,Cavazzana Marina²³⁴^ORCID,Mallebranche Coralie¹²¹³^ORCID,Visvikis Orane¹^ORCID,Kracker Sven²¹⁴^ORCID,Moshous Despina¹⁵¹⁶^ORCID,Verhoeyen Els¹⁶^ORCID,Boyer Laurent¹^ORCID

Affiliation:

1. Université Côte d’Azur, INSERM, C3M 1 , Nice, France

2. Université Paris Cité 2 , Paris, France

3. Imagine Institute, INSERM UMR 1163 3 , Paris, France

4. Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM 4 , Paris, France

5. Université Côte d’Azur, Centre Hospitalier Universitaire de Nice 5 , Nice, France

6. Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111 6 , Lyon, France

7. Université Claude Bernard Lyon 1, CNRS UMR5308, École normale supérieure de Lyon 7 , Lyon, France

8. Université Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire 8 , Sophia-Antipolis, France

9. Centre de Référence National des Cytopénies Autoimmunes de l’Enfant, Pediatric Hematologic Unit, Centre d’Investigation Clinique Plurithématique INSERM 1401, University Hospital of Bordeaux 9 , Bordeaux, France

10. Necker Hospital, Pediatric Hematology-Immunology and Rheumatology Unit, Assistance Publique-Hôpitaux de Paris 10 , Paris, France

11. Collège de France 11 , Paris, France

12. Université d’Angers, Université de Nantes, Inserm, CNRS, CRCI2NA, SFR ICAT 12 , Angers, France

13. Centre Hospitalier Universitaire Angers, Pediatric Immuno-Hemato-Oncology Unit 13 , Angers, France

14. Laboratory of Human Lymphohematopoiesis, Imagine Institute, INSERM UMR 1163 14 , Paris, France

15. Laboratoire Dynamique du Génome et Système Immunitaire, Imagine Institute, INSERM UMR 1163 15 , Paris, France

16. Centre de Référence des Déficits Immunitaires Héréditaires, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Université Paris Cité 16 , Paris, France

Abstract

A growing number of patients presenting severe combined immunodeficiencies attributed to monoallelic RAC2 variants have been identified. The expression of the RHO GTPase RAC2 is restricted to the hematopoietic lineage. RAC2 variants have been described to cause immunodeficiencies associated with high frequency of infection, leukopenia, and autoinflammatory features. Here, we show that specific RAC2 activating mutations induce the NLRP3 inflammasome activation leading to the secretion of IL-1β and IL-18 from macrophages. This activation depends on the activation state of the RAC2 variant and is mediated by the downstream kinase PAK1. Inhibiting the RAC2–PAK1–NLRP3 inflammasome pathway might be considered as a potential treatment for these patients.

Funder

Fondation pour la Recherche Médicale

Agence Nationale de la Recherche

E-Rare Joint Transnational Call for Proposals 2015

Association pour la Recherche sur le Cancer

Université Côte d’Azur

France Génomique National Infrastructure

Canceropôle PACA

Publisher

Rockefeller University Press

Link

https://rupress.org/jem/article-pdf/doi/10.1084/jem.20231562/1932107/jem_20231562.pdf

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