Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation
| Autor: | Michael J. Primiano, Andrea G Bree, Paul D. Bonin, Aiping Jiao, Stephen W. J. Wang, J. Perry Hall, David Hepworth, Ken Dower, Julia A. Guzova, Bruce Allen Lefker, Cedric Hubeau, Eicke Latz, Leah Cushing, Brian G. Monks, Lih-Ling Lin, Michael R. Bowman, Matthew Mangan |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Inflammasomes Interleukin-1beta Dermatitis Pharmacology Pathogenesis Mice immunology [Inflammation] Interleukin-1alpha administration & dosage [Heterocyclic Compounds 4 or More Rings] Immunology and Allergy Medicine metabolism [Interleukin-1alpha] therapeutic use [Sulfones] Sulfones immunology [Interleukin-1beta] Sulfonamides integumentary system Interleukin-18 Inflammasome administration & dosage [Sulfones] immunology [Pneumonia] Indenes Cytokines medicine.symptom Signal transduction pharmacology [Sulfones] medicine.drug Signal Transduction antagonists & inhibitors [Inflammasomes] Immunology drug effects [Immunity Innate] Inflammation Heterocyclic Compounds 4 or More Rings Proinflammatory cytokine physiopathology [Dermatitis] 03 medical and health sciences In vivo Immunity antagonists & inhibitors [Interleukin-1alpha] drug therapy [Pneumonia] NLR Family Pyrin Domain-Containing 3 Protein Animals Humans ddc:610 Furans antagonists & inhibitors [NLR Family Pyrin Domain-Containing 3 Protein] Innate immune system antagonists & inhibitors [Cytokines] business.industry MCC-950 antagonists & inhibitors [Interleukin-1beta] drug therapy [Inflammation] Pneumonia drug therapy [Dermatitis] therapeutic use [Heterocyclic Compounds 4 or More Rings] physiopathology [Pneumonia] antagonists & inhibitors [Interleukin-18] Immunity Innate Disease Models Animal 030104 developmental biology immunology [Cytokines] immunology [Dermatitis] metabolism [Interleukin-18] physiopathology [Inflammation] business pharmacology [Heterocyclic Compounds 4 or More Rings] |
| Zdroj: | The journal of immunology 197(6), 2421-2433 (2016). doi:10.4049/jimmunol.1600035 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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