RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation
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.
Authors
- Paul Chaintreuil (ORCID: https://orcid.org/0000-0002-4845-7304)
- Els Verhoeyen (ORCID: https://orcid.org/0000-0001-9224-5491)
- Chantal Lagresle‐Peyrou (ORCID: https://orcid.org/0000-0002-2216-6453)
- Marina Cavazzana (ORCID: https://orcid.org/0000-0002-0264-0891)
- Patrick M. Munro (ORCID: https://orcid.org/0000-0003-4283-4671)
- Valérie Giordanengo (ORCID: https://orcid.org/0000-0002-5114-1124)
- Céline Loubatier (ORCID: https://orcid.org/0000-0001-5727-342X)
- Nathalie Aladjidi (ORCID: https://orcid.org/0000-0003-0231-4460)
- Despina Moshous (ORCID: https://orcid.org/0000-0001-6719-3693)
- Alain Fischer (ORCID: https://orcid.org/0000-0003-4025-5983)
- Valentine Marion (ORCID: https://orcid.org/0000-0002-3215-6590)
- Marie Couralet (ORCID: https://orcid.org/0000-0002-4581-8418)
- Johan Courjon (ORCID: https://orcid.org/0000-0002-0445-5104)
- Orane Visvikis (ORCID: https://orcid.org/0000-0001-7719-5836)
- Sven Kracker (ORCID: https://orcid.org/0000-0003-4543-8236)
- Arnaud Jacquel (ORCID: https://orcid.org/0000-0001-5062-8048)
- Boris Bessot
- Pascal Barbry (ORCID: https://orcid.org/0000-0001-9632-6483)
- Pauline Bronnec (ORCID: https://orcid.org/0009-0002-1942-7621)
- Coralie Mallebranche (ORCID: https://orcid.org/0000-0002-8385-4057)
- Julie Contenti (ORCID: https://orcid.org/0000-0002-1532-6180)
- Nataël Sorel
- Anne Doye (ORCID: https://orcid.org/0000-0001-6466-9326)
- Laurent Boyer (ORCID: https://orcid.org/0000-0002-1375-1706)
- Ludovic Batistic (ORCID: https://orcid.org/0000-0002-3732-0783)
- Rayana Chirara (ORCID: https://orcid.org/0000-0001-8642-192X)
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Collège de France (FR)
- Université Côte d'Azur (FR)
- Université Paris Cité (FR)
- Centre Hospitalier Universitaire de Nice (FR)
- Université Paris Nanterre (FR)
- Centre de Référence Déficits Immunitaires Héréditaires (FR)
- Sorbonne Paris Cité (FR)
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Centre Hospitalier Universitaire d'Angers (FR)
- Hôpitaux Universitaires Paris-Ouest (FR)
- Polyclinique de Bordeaux-Tondu (FR)
- Institut de Pharmacologie Moléculaire et Cellulaire (FR)
- Centre International de Recherche en Infectiologie (FR)
- Institut des Maladies Génétiques Imagine (FR)
- Université d'Angers (FR)
- Nantes Université (FR)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1084/jem.20231562
- Citations
- 7
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- Association pour la Recherche sur le Cancer
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Centre National de la Recherche Scientifique
- Canceropôle PACA
- Université Côte d’Azur