138812 20240321220513.0 10.4049/jimmunol.1600035 doi pmid:27521339 pmid 0022-1767 ISSN 1047-7381 ISSN 1048-3233 ISSN 1550-6606 ISSN altmetric:28698417 altmetric DZNE-2020-05134 English 610 Primiano, Michael J 0 Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation. Bethesda, Md. 2016 Soc. online Crossref The American Association of Immunologists 2016-08-12 print Crossref The American Association of Immunologists 2016-09-15 article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1585919153_20528 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote A critical component of innate immune response to infection and tissue damage is the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome, and this pathway and its activation products have been implicated in the pathophysiology of a variety of diseases. NLRP3 inflammasome activation leads to the cleavage of pro-IL-1β and pro-IL-18, as well as the subsequent release of biologically active IL-1β, IL-18, and other soluble mediators of inflammation. In this study, we further define the pharmacology of the previously reported NLRP3 inflammasome-selective, IL-1β processing inhibitor CP-456,773 (also known as MCC950), and we demonstrate its efficacy in two in vivo models of inflammation. Specifically, we show that in human and mouse innate immune cells CP-456,773 is an inhibitor of the cellular release of IL-1β, IL-1α, and IL-18, that CP-456,773 prevents inflammasome activation induced by disease-relevant soluble and crystalline NLRP3 stimuli, and that CP-456,773 inhibits R848- and imiquimod-induced IL-1β release. In mice, CP-456,773 demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS plus ATP in a manner that is proportional to the free/unbound concentrations of the drug, thereby establishing an in vivo pharmacokinetic/pharmacodynamic model for CP-456,773. Furthermore, CP-456,773 reduces ear swelling in an imiquimod cream-induced mouse model of skin inflammation, and it reduces airway inflammation in mice following acute challenge with house dust mite extract. These data implicate the NLRP3 inflammasome in the pathogenesis of dermal and airway inflammation, and they highlight the utility of CP-456,773 for interrogating the contribution of the NLRP3 inflammasome and its outputs in preclinical models of inflammation and disease. 342 - Disease Mechanisms and Model Systems (POF3-342) G:(DE-HGF)POF3-342 POF3-342 POF III 0 Dataset connected to CrossRef, PubMed, Cytokines NLM Chemicals Heterocyclic Compounds, 4 or More Rings NLM Chemicals Inflammasomes NLM Chemicals Interleukin-18 NLM Chemicals Interleukin-1alpha NLM Chemicals Interleukin-1beta NLM Chemicals MCC-950 NLM Chemicals NLR Family, Pyrin Domain-Containing 3 Protein NLM Chemicals Sulfones NLM Chemicals Furans MeSH Animals MeSH Cytokines: antagonists & inhibitors MeSH Cytokines: immunology MeSH Dermatitis: drug therapy MeSH Dermatitis: immunology MeSH Dermatitis: physiopathology MeSH Disease Models, Animal MeSH Heterocyclic Compounds, 4 or More Rings: administration & dosage MeSH Heterocyclic Compounds, 4 or More Rings: pharmacology MeSH Heterocyclic Compounds, 4 or More Rings: therapeutic use MeSH Humans MeSH Immunity, Innate: drug effects MeSH Inflammasomes: antagonists & inhibitors MeSH Inflammation: drug therapy MeSH Inflammation: immunology MeSH Inflammation: physiopathology MeSH Interleukin-18: antagonists & inhibitors MeSH Interleukin-18: metabolism MeSH Interleukin-1alpha: antagonists & inhibitors MeSH Interleukin-1alpha: metabolism MeSH Interleukin-1beta: antagonists & inhibitors MeSH Interleukin-1beta: immunology MeSH Mice MeSH NLR Family, Pyrin Domain-Containing 3 Protein: antagonists & inhibitors MeSH Pneumonia: drug therapy MeSH Pneumonia: immunology MeSH Pneumonia: physiopathology MeSH Signal Transduction MeSH Sulfones: administration & dosage MeSH Sulfones: pharmacology MeSH Sulfones: therapeutic use MeSH Indenes MeSH Sulfonamides MeSH Lefker, Bruce A 1 Bowman, Michael R 2 Bree, Andrea G 3 Hubeau, Cedric 4 Bonin, Paul D 5 Mangan, Matthew P:(DE-2719)2810930 6 dzne Dower, Ken 7 Monks, Brian G 8 Cushing, Leah 9 Wang, Stephen 10 Guzova, Julia 11 Jiao, Aiping 12 Lin, Lih-Ling 13 Latz, Eicke P:(DE-2719)2000062 14 dzne Hepworth, David 15 Hall, J Perry P:(DE-HGF)0 16 Corresponding author 10.4049/jimmunol.1600035 : The American Association of Immunologists, 2016-08-12 6 2421-2433 journal-article Crossref The Journal of Immunology 197 2016 0022-1767 10.4049/jimmunol.1600035 Vol. 197, no. 6, p. 2421 - 2433 PERI:(DE-600)1475085-5 6 197:6<2421 - 2433 2421-2433 The journal of immunology 197 2016 0022-1767 oai:pub.dzne.de:138812 VDB Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 6 P:(DE-2719)2810930 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 14 P:(DE-2719)2000062 DE-HGF Forschungsbereich Gesundheit Erkrankungen des Nervensystems G:(DE-HGF)POF3-340 G:(DE-HGF)POF3-342 G:(DE-HGF)POF3-300 Disease Mechanisms and Model Systems 0 2016 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS DBCoverage StatID:(DE-HGF)0300 StatID Medline DBCoverage StatID:(DE-HGF)0310 StatID NCBI Molecular Biology Database JCR StatID:(DE-HGF)0100 StatID J IMMUNOL : 2017 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search Peer Review StatID:(DE-HGF)0030 StatID ASC DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List WoS StatID:(DE-HGF)0110 StatID Science Citation Index DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection WoS StatID:(DE-HGF)0111 StatID Science Citation Index Expanded DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - 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