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Article Dans Une Revue Science Signaling Année : 2024

NLRP12 interacts with NLRP3 to block the activation of the human NLRP3 inflammasome

Jared Coombs
Alina Zamoshnikova
Caroline Holley
Madhavi Maddugoda
Daniel Eng Thiam Teo
Connie Ross
Manasa Mellacheruvu
Leonhard Heinz
Sabrina Burgener
Stefan Emming
Dave Boucher
Kate Schroder

Résumé

Inflammasomes are multiprotein complexes that drive inflammation and contribute to protective immunity against pathogens and immune pathology in autoinflammatory diseases. Inflammasomes assemble when an inflammasome scaffold protein senses an activating signal and forms a signaling platform with the inflammasome adaptor protein ASC. The NLRP subfamily of NOD-like receptors (NLRs) includes inflammasome nucleators (such as NLRP3) and also NLRP12, which is genetically linked to familial autoinflammatory disorders that resemble diseases caused by gain-of-function NLRP3 mutants that generate a hyperactive NLRP3 inflammasome. We performed a screen to identify ASC inflammasome–nucleating proteins among NLRs that have the canonical pyrin-NACHT-LRR domain structure. Only NLRP3 and NLRP6 could initiate ASC polymerization to form “specks,” and NLRP12 failed to nucleate ASC polymerization. However, wild-type NLRP12 inhibited ASC inflammasome assembly induced by wild-type and gain-of-function mutant NLRP3, an effect not seen with disease-associated NLRP12 mutants. The capacity of NLRP12 to suppress NLRP3 inflammasome assembly was limited to human NLRP3 and was not observed for wild-type murine NLRP3. Furthermore, peripheral blood mononuclear cells from patients with an NLRP12 mutant–associated inflammatory disorder produced increased amounts of the inflammatory cytokine IL-1β in response to NLRP3 stimulation. Thus, our findings provide insights into NLRP12 biology and suggest that NLRP3 inhibitors in clinical trials for NLRP3-driven diseases may also be effective in treating NLRP12-associated autoinflammatory diseases.
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Dates et versions

hal-04543195 , version 1 (12-04-2024)

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Citer

Jared Coombs, Alina Zamoshnikova, Caroline Holley, Madhavi Maddugoda, Daniel Eng Thiam Teo, et al.. NLRP12 interacts with NLRP3 to block the activation of the human NLRP3 inflammasome. Science Signaling, 2024, 17 (820), ⟨10.1126/scisignal.abg8145⟩. ⟨hal-04543195⟩
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