Published October 7, 2024
| Version v1
Journal article
RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation
Creators
- Doye, Anne
- Chaintreuil, Paul
- Lagresle-Peyrou, Chantal
- Batistic, Ludovic
- Marion, Valentine
- Munro, Patrick
- Loubatier, Celine
- Chirara, Rayana
- Sorel, Nataël
- Bessot, Boris
- Bronnec, Pauline
- Contenti, Julie
- Courjon, Johan
- Giordanengo, Valerie
- Jacquel, Arnaud
- Barbry, Pascal
- Couralet, Marie
- Aladjidi, Nathalie
- Fischer, Alain
- Cavazzana, Marina
- Mallebranche, Coralie
- Visvikis, Orane
- Kracker, Sven
- Moshous, Despina
- Verhoeyen, Els
- Boyer, Laurent
Contributors
Others:
- Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111 , Lyon, France.
- Inflammasome, Infections bactériennes et autoinflammation ; Inflammasome, Bacterial Infections and Autoinflammation [CIRI] (CIRI-I2BA) ; Centre International de Recherche en Infectiologie (CIRI) ; École normale supérieure de Lyon (ENS de Lyon) ; Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon) ; Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Centre National de la Recherche Scientifique (CNRS)
- Université Côte d'Azur (UniCA)
- Institut de pharmacologie moléculaire et cellulaire (IPMC) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UniCA)
Description
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.
Abstract
International audienceAdditional details
Identifiers
- URL
- https://hal.science/hal-04877028
- URN
- urn:oai:HAL:hal-04877028v1
Origin repository
- Origin repository
- UNICA