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@ARTICLE{Primiano:138812,
      author       = {Primiano, Michael J and Lefker, Bruce A and Bowman, Michael
                      R and Bree, Andrea G and Hubeau, Cedric and Bonin, Paul D
                      and Mangan, Matthew and Dower, Ken and Monks, Brian G and
                      Cushing, Leah and Wang, Stephen and Guzova, Julia and Jiao,
                      Aiping and Lin, Lih-Ling and Latz, Eicke and Hepworth, David
                      and Hall, J Perry},
      title        = {{E}fficacy and {P}harmacology of the {NLRP}3 {I}nflammasome
                      {I}nhibitor {CP}-456,773 ({CRID}3) in {M}urine {M}odels of
                      {D}ermal and {P}ulmonary {I}nflammation.},
      journal      = {The journal of immunology},
      volume       = {197},
      number       = {6},
      issn         = {0022-1767},
      address      = {Bethesda, Md.},
      publisher    = {Soc.},
      reportid     = {DZNE-2020-05134},
      pages        = {2421-2433},
      year         = {2016},
      abstract     = {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.},
      keywords     = {Furans / Animals / Cytokines: antagonists $\&$ inhibitors /
                      Cytokines: immunology / Dermatitis: drug therapy /
                      Dermatitis: immunology / Dermatitis: physiopathology /
                      Disease Models, Animal / Heterocyclic Compounds, 4 or More
                      Rings: administration $\&$ dosage / Heterocyclic Compounds,
                      4 or More Rings: pharmacology / Heterocyclic Compounds, 4 or
                      More Rings: therapeutic use / Humans / Immunity, Innate:
                      drug effects / Inflammasomes: antagonists $\&$ inhibitors /
                      Inflammation: drug therapy / Inflammation: immunology /
                      Inflammation: physiopathology / Interleukin-18: antagonists
                      $\&$ inhibitors / Interleukin-18: metabolism /
                      Interleukin-1alpha: antagonists $\&$ inhibitors /
                      Interleukin-1alpha: metabolism / Interleukin-1beta:
                      antagonists $\&$ inhibitors / Interleukin-1beta: immunology
                      / Mice / NLR Family, Pyrin Domain-Containing 3 Protein:
                      antagonists $\&$ inhibitors / Pneumonia: drug therapy /
                      Pneumonia: immunology / Pneumonia: physiopathology / Signal
                      Transduction / Sulfones: administration $\&$ dosage /
                      Sulfones: pharmacology / Sulfones: therapeutic use / Indenes
                      / Sulfonamides / 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)},
      cin          = {AG Latz},
      ddc          = {610},
      cid          = {I:(DE-2719)1013024},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:27521339},
      doi          = {10.4049/jimmunol.1600035},
      url          = {https://pub.dzne.de/record/138812},
}