title: Caspase-1 activation by NLRP3 inflammasome dampens IL-33-dependent house dust mite-induced allergic lung inflammation.
abstract: The cysteine protease caspase-1 (Casp-1) contributes to innate immunity through the assembly of NLRP3, NLRC4, AIM2, and NLRP6 inflammasomes. Here we ask whether caspase-1 activation plays a regulatory role in house dust mite (HDM)-induced experimental allergic airway inflammation. We report enhanced airway inflammation in caspase-1-deﬁcient mice exposed to HDM with a marked eosinophil recruitment, increased expression of IL-4, IL-5, IL-13, as well as full-length and bioactive IL-33. Furthermore, mice deficient for NLRP3 failed to control eosinophil influx in the airways and displayed augmented Th2 cytokine and chemokine levels, suggesting that the NLPR3 inflammasome complex controls HDM-induced inflammation. IL-33 neutralization by administration of soluble ST2 receptor inhibited the enhanced allergic inflammation, while administration of recombinant IL-33 during challenge phase enhanced allergic inflammation in caspase-1-deficient mice. Therefore, we show that caspase-1, NLRP3, and ASC, but not NLRC4, contribute to the upregulation of allergic lung inflammation. Moreover, we cannot exclude an effect of caspase-11, because caspase-1-deficient mice are deficient for both caspases. Mechanistically, absence of caspase-1 is associated with increased expression of IL-33, uric acid, and spleen tyrosine kinase (Syk) production. This study highlights a critical role of caspase-1 activation and NLPR3/ASC inflammasome complex in the down-modulation of IL-33 in vivo and in vitro, thereby regulating Th2 response in HDM-induced allergic lung inﬂammation.
authors.affiliation: Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, F-45071 Orleans-Cedex2, France Artimmune SAS, 45100 Orléans, France.
authors.forename: Fahima
authors.initials: F
authors.lastname: Madouri
authors.affiliation: Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, F-45071 Orleans-Cedex2, France.
authors.forename: Noëlline
authors.initials: N
authors.lastname: Guillou
authors.affiliation: Artimmune SAS, 45100 Orléans, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Fauconnier
authors.affiliation: Artimmune SAS, 45100 Orléans, France.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Marchiol
authors.affiliation: Artimmune SAS, 45100 Orléans, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rouxel
authors.affiliation: Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, F-45071 Orleans-Cedex2, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Chenuet
authors.affiliation: Artimmune SAS, 45100 Orléans, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ledru
authors.affiliation: Faculté de Médecine, University of Bourgogne, Dijon, France INSERM, U866, Dijon, France Centre Georges François Leclerc, Dijon, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.affiliation: Faculté de Médecine, University of Bourgogne, Dijon, France INSERM, U866, Dijon, France Centre Georges François Leclerc, Dijon, France.
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.affiliation: CIIL - Center for Infection and Immunity of Lille, INSERM U1019, Institut Pasteur, Lille, France.
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.affiliation: Division of Rheumatology, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033, USA Clinical Immunology Section, Third Affiliated Hospital at Sun Yat-Sen University, Guangzhou 510630, China.
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
authors.affiliation: Artimmune SAS, 45100 Orléans, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Trovero
authors.affiliation: Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, F-45071 Orleans-Cedex2, France.
authors.forename: Valérie F J
authors.initials: VF
authors.lastname: Quesniaux
authors.affiliation: Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, F-45071 Orleans-Cedex2, France.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, F-45071 Orleans-Cedex2, France Artimmune SAS, 45100 Orléans, France dieudo.togbe@artimmune.com dtogbe@cnrs-orleans.fr.
authors.forename: Dieudonnée
authors.initials: D
authors.lastname: Togbe
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000172:deficiency / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006967:Hypersensitivity / Q000201:enzymology / Q000276:immunology* / Q000469:parasitology; D007109:Immunity / Q000187:drug effects; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000276:immunology* / Q000473:pathology; D000067596:Interleukin-33 / Q000276:immunology*; D008168:Lung / Q000201:enzymology / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D039981:Pyroglyphidae / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D014527:Uric Acid / Q000378:metabolism
chemical_list: D039741:Antigens, Dermatophagoides; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D000067596:Interleukin-33; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011993:Recombinant Fusion Proteins; D014527:Uric Acid; D020170:Caspase 1
keywords: IL-33; allergic asthma; caspase-1; house dust mite; inflammasomes; spleen tyrosine kinase (Syk); uric acid