TY  - JOUR
AU  - Primiano, Michael J
AU  - Lefker, Bruce A
AU  - Bowman, Michael R
AU  - Bree, Andrea G
AU  - Hubeau, Cedric
AU  - Bonin, Paul D
AU  - Mangan, Matthew
AU  - Dower, Ken
AU  - Monks, Brian G
AU  - Cushing, Leah
AU  - Wang, Stephen
AU  - Guzova, Julia
AU  - Jiao, Aiping
AU  - Lin, Lih-Ling
AU  - Latz, Eicke
AU  - Hepworth, David
AU  - Hall, J Perry
TI  - Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation.
JO  - The journal of immunology
VL  - 197
IS  - 6
SN  - 0022-1767
CY  - Bethesda, Md.
PB  - Soc.
M1  - DZNE-2020-05134
SP  - 2421-2433
PY  - 2016
AB  - 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.
KW  - Furans
KW  - Animals
KW  - Cytokines: antagonists & inhibitors
KW  - Cytokines: immunology
KW  - Dermatitis: drug therapy
KW  - Dermatitis: immunology
KW  - Dermatitis: physiopathology
KW  - Disease Models, Animal
KW  - Heterocyclic Compounds, 4 or More Rings: administration & dosage
KW  - Heterocyclic Compounds, 4 or More Rings: pharmacology
KW  - Heterocyclic Compounds, 4 or More Rings: therapeutic use
KW  - Humans
KW  - Immunity, Innate: drug effects
KW  - Inflammasomes: antagonists & inhibitors
KW  - Inflammation: drug therapy
KW  - Inflammation: immunology
KW  - Inflammation: physiopathology
KW  - Interleukin-18: antagonists & inhibitors
KW  - Interleukin-18: metabolism
KW  - Interleukin-1alpha: antagonists & inhibitors
KW  - Interleukin-1alpha: metabolism
KW  - Interleukin-1beta: antagonists & inhibitors
KW  - Interleukin-1beta: immunology
KW  - Mice
KW  - NLR Family, Pyrin Domain-Containing 3 Protein: antagonists & inhibitors
KW  - Pneumonia: drug therapy
KW  - Pneumonia: immunology
KW  - Pneumonia: physiopathology
KW  - Signal Transduction
KW  - Sulfones: administration & dosage
KW  - Sulfones: pharmacology
KW  - Sulfones: therapeutic use
KW  - Indenes
KW  - Sulfonamides
KW  - Cytokines (NLM Chemicals)
KW  - Heterocyclic Compounds, 4 or More Rings (NLM Chemicals)
KW  - Inflammasomes (NLM Chemicals)
KW  - Interleukin-18 (NLM Chemicals)
KW  - Interleukin-1alpha (NLM Chemicals)
KW  - Interleukin-1beta (NLM Chemicals)
KW  - MCC-950 (NLM Chemicals)
KW  - NLR Family, Pyrin Domain-Containing 3 Protein (NLM Chemicals)
KW  - Sulfones (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27521339
DO  - DOI:10.4049/jimmunol.1600035
UR  - https://pub.dzne.de/record/138812
ER  -