Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 10, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20201466
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Funding
- European Research Council [802041, 801823, 616050]
- Institut national de la sante et de la recherche medicale ATIP-Avenir program
- Incentive Grant for Scientific Research of the Fund for Scientific Research of the Fonds De La Recherche Scientifique - FNRS [F.4508.18]
- Fund for Strategic Fundamental Research-Walloon Excellence in Lifesciences and Biotechnology [CR-2017s-04]
- Acteria Foundation
- Agence Nationale de la Recherche Young Female Researchers [ANR-16-CE15-0012]
- Institut Pasteur
- Institut national de la sante et de la recherche medicale
- Fondation pour la Recherche Medicale
- Arthritis National Research Foundation
- National Institutes of Health [K99 AI110645, R01 AI132494, R01 AR067145, R01 AI125567, U19 AI104209, R01 AI15586901, R01 DK113592]
- Institut national de la sante et de la recherche m'edicale
- American Academy of Allergy Asthma and Immunology Foundation
- Agence Nationale de la Recherche (ANR) [ANR-16-CE15-0012] Funding Source: Agence Nationale de la Recherche (ANR)
- European Research Council (ERC) [801823, 616050, 802041] Funding Source: European Research Council (ERC)
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Gain-of-function mutations in NLRP3 gene cause CAPS, with neutrophils potentially being the main cellular drivers of CAPS pathology.
Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as cryopyrin-associated periodic syndromes (CAPS). Treatment of CAPS patients with IL-1-targeted therapies is effective, confirming a central pathogenic role for IL-1 beta. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1 beta production in CAPS remains elusive. Previous reports suggested an important role for mast cells (MCs) in this process. Here, we report that, in mice, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS. Furthermore, in patients with clinically established CAPS, we show that skin-infiltrating neutrophils represent a substantial biological source of IL-1 beta. Together, our data indicate that neutrophils, rather than MCs, can represent the main cellular drivers of CAPS pathology.
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