Frontline Science: Multiple cathepsins promote inflammasome-independent, particle-induced cell death during NLRP3-dependent IL-1β activation.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Orlowski, GM; Sharma, S; Colbert, JD; Bogyo, M; Robertson, SA; Kataoka, H; Chan, FK; Rock, KL

Published Date

  • July 2017

Published In

Volume / Issue

  • 102 / 1

Start / End Page

  • 7 - 17

PubMed ID

  • 28087651

Pubmed Central ID

  • 28087651

Electronic International Standard Serial Number (EISSN)

  • 1938-3673

Digital Object Identifier (DOI)

  • 10.1189/jlb.3HI0316-152R

Language

  • eng

Conference Location

  • United States