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

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Severe combined immunodeficiencies (SCIDs) are increasingly linked to monoallelic RAC2 variants.
• RAC2, a RHO GTPase, is crucial for hematopoietic lineage function.
• RAC2 variants cause immunodeficiency, recurrent infections, leukopenia, and autoinflammation.

Purpose of the Study:

• To investigate the molecular mechanisms by which RAC2 variants contribute to autoinflammatory features.
• To determine if RAC2 activating mutations trigger inflammasome activation.
• To identify potential therapeutic targets for RAC2-related disorders.

Main Methods:

• Analysis of RAC2 variant activation states.
• Assessment of downstream signaling pathways, including PAK1.
• Measurement of inflammasome components (NLRP3) and cytokine secretion (IL-1β, IL-18) from macrophages.

Main Results:

• Specific activating RAC2 mutations induce NLRP3 inflammasome activation in macrophages.
• This activation is dependent on the RAC2 variant's activation state.
• The downstream kinase PAK1 mediates the RAC2-induced inflammasome activation.

Conclusions:

• RAC2 activating mutations directly trigger the NLRP3 inflammasome pathway.
• The RAC2-PAK1-NLRP3 axis is a key mediator of inflammation in these patients.
• Inhibition of the RAC2-PAK1-NLRP3 pathway presents a potential therapeutic strategy.