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Dryad

Data from: RAC2 gain of function variants causing inborn error of immunity drive NLRP3 inflammasome activation

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Aug 08, 2024 version files 55.12 MB

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 RAC2 activating mutations induce the NLRP3 inflammasome leading to the secretion of IL-1 and IL-18 from macrophages. This induction depends on the RAC2 mutation and in particular their activation state. This suggests that inhibiting the RAC2-PAK1-NLRP3 inflammasome pathway might be considered as a potential treatment for these patients.

To investigate in depth the impact of the activating variant RAC2 A59S we performed a single cell RNAseq analysis of blood circulating cells. This analysis showed increased numbers of both classical and non classical monocytes as well as myeloid dendritic cells when compared to a healthy control. In addition, and supporting our hypothesis, NLRP3 and IL-1b expression levels were increased in both monocytes and myeloid dendritic cells, while their expression in lymphocytes was not affected in our analysis.

To further confirm our data, we compared monocytes isolated from PBMCs of patients harboring the RAC2 A59S with monocytes isolated from RAC2 E62K mutation. In both cases, the PBMCs were collected and frozen using the same protocol and PBMCs from patients and control healthy donors were processed in parallel.

In general, the results of this study identified the RAC2 A59S mutation as a gain of function variant activating NLRP3.