title: Frontline Science: Multiple cathepsins promote inflammasome-independent, particle-induced cell death during NLRP3-dependent IL-1β activation.
abstract: Sterile particles cause several chronic, inflammatory diseases, characterized by repeating cycles of particle phagocytosis and inflammatory cell death. Recent studies have proposed that these processes are driven by the NLRP3 inflammasome, a platform activated by phagocytosed particles, which controls both caspase-1-dependent cell death (pyroptosis) and mature IL-1β secretion. After phagocytosis, particles can disrupt lysosomes, and inhibitor studies have suggested that the resulting release of a lysosomal protease-cathepsin B-into the cytosol somehow activates NLRP3. However, using primary murine macrophages, we found that particle-induced cell death occurs independent of NLRP3/caspase-1 and depends instead on multiple, redundant cathepsins. In contrast, nigericin, a soluble activator of NLRP3 inflammasomes, induced cell death that was dependent on the NLRP3. Interestingly, nigericin-induced cell death depended partly on a single cathepsin, cathepsin X. By inhibiting or silencing multiple cathepsins in macrophages, several key proinflammatory events induced by sterile particles are blocked, including cell death, pro-IL-1β production, and IL-1β secretion. These data suggest that cathepsins might be potential therapeutic targets in particulate-mediated inflammatory disease. In support of this concept, we find that a broad-spectrum cathepsin inhibitor can suppress particle-induced IL-1-dependent peritonitis.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Orlowski
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Colbert
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA; and.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
authors.affiliation: Sandler Center for Drug Discovery, University of California, San Francisco, California, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Robertson
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kataoka
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Francis K
authors.initials: FK
authors.lastname: Chan
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA; kenneth.rock@umassmed.edu.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rock
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism*; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D052638:Particulate Matter / Q000009:adverse effects* / Q000494:pharmacology; D010538:Peritonitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D052638:Particulate Matter; D002403:Cathepsins; C000602812:cathepsin X, mouse; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D020170:Caspase 1
keywords: caspase-1; inflammation; macrophage; peritonitis; pyroptosis