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

• Published in: The Journal of experimental medicine Vol. 221; no. 10
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States 07.10.2024
• Subjects: Animals; Gain of Function Mutation; Humans; Inflammasomes - immunology; Inflammasomes - metabolism; Interleukin-18 - genetics; Interleukin-18 - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Macrophages - immunology; Macrophages - metabolism; Mice; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; p21-Activated Kinases - genetics; p21-Activated Kinases - metabolism; rac GTP-Binding Proteins - genetics; rac GTP-Binding Proteins - metabolism; RAC2 GTP-Binding Protein; Signal Transduction
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20231562

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.