Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation - Université de Paris - Faculté de Santé Access content directly
Journal Articles Journal of Experimental Medicine Year : 2024

Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation

Elodie Chatre
Etienne Merlin
Agnès Duquesne
Gilles Grateau
  • Function : Author
Léa Savey
Solène Poutrel
Samuel Ardois
Olivier Richer
Laurence Cuisset
Isabelle Touitou
Matthias Geyer
Sophie Georgin-Lavialle

Abstract

NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments. Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on the signals governing their activation, correlating partly with the symptom severity. We identify a new group of NLRP3 mutants responding to the activation signal without priming, associated with frequent misdiagnoses. Our results identify key NLRP3 residues controlling inflammasome activity and sensitivity to inhibitors, and antagonistic mechanisms with broader efficacy for therapeutic strategies. They provide new insights into NLRP3 activation, an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and drug development.
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Dates and versions

hal-04536945 , version 1 (08-04-2024)

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Camille Cosson, Romane Riou, Danish Patoli, Tingting Niu, Amaury Rey, et al.. Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation. Journal of Experimental Medicine, 2024, 221 (5), pp.e20231200. ⟨10.1084/jem.20231200⟩. ⟨hal-04536945⟩
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