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- W4313354630 abstract "Abstract IL-1β mediates a multitude of debilitating, and sometimes fatal, acute and chronic inflammatory diseases. However, existing therapies for these diseases target IL-1β directly, suppressing both its pathologic and protective activities. We propose that cathepsins are therapeutic targets specific to IL-1β-mediated inflammatory diseases caused by sterile particulates. These particulates, such as cholesterol crystals (atherosclerosis), silica (silicosis) and monosodium urate (gout), activate the NLRP3 inflammasome in immune cells, leading to active IL-1β secretion. Rather than conferring protection, this response causes disease. Here, we show that a bioavailable inhibitor of cathepsins B, L & C, called K777, specifically suppresses particulate-mediated IL-1β production by primary macrophages. Using primary and immortalized macrophages deficient in cathepsins B & L, we demonstrate these proteases are critical targets likely responsible for much of K777’s effect. Moreover, we show for the first time that, unlike other NLRP3 stimuli, particulate-mediated inflammatory cell death is inflammasome-independent and cathepsin-dependent. Finally, in a murine model of acute peritonitis, both subcutaneous and intravenous K777 treatment substantially and preferentially reduced IL-1β-dependent neutrophil influx caused by particulate stimuli. Together, these data are the first to translate cathepsin inhibition in vitro into an in vivo model, validating cathepsins as potentially selective therapeutic targets in particulate-mediated inflammatory disease." @default.
- W4313354630 created "2023-01-06" @default.
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- W4313354630 creator A5050403187 @default.
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- W4313354630 date "2013-05-01" @default.
- W4313354630 modified "2023-09-30" @default.
- W4313354630 title "Validating cathepsins as selective therapeutic targets for the treatment of particulate-mediated sterile inflammatory disease. (P1373)" @default.
- W4313354630 doi "https://doi.org/10.4049/jimmunol.190.supp.63.41" @default.
- W4313354630 hasPublicationYear "2013" @default.
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