| First Author | Campden RI | Year | 2022 |
| Journal | J Biol Chem | Volume | 298 |
| Issue | 1 | Pages | 101459 |
| PubMed ID | 34864055 | Mgi Jnum | J:325372 |
| Mgi Id | MGI:6853776 | Doi | 10.1016/j.jbc.2021.101459 |
| Citation | Campden RI, et al. (2021) Extracellular cathepsin Z signals through the alpha5 integrin and augments NLRP3 inflammasome activation. J Biol Chem 298(1):101459 |
| abstractText | Respiratory silicosis is a preventable occupational disease that develops secondary to the aspiration of crystalline silicon dioxide (silica) into the lungs, activation of the NLRP3 inflammasome, and IL-1beta production. Cathepsin Z has been associated with the development of inflammation and IL-1beta production; however, the mechanism of how cathepsin Z leads to IL-1beta production is unknown. Here, the requirement for cathepsin Z in silicosis was determined using WT mice and mice deficient in cathepsin Z. The activation of the NLRP3 inflammasome in macrophages was studied using WT and cathepsin Z-deficient bone marrow-derived murine dendritic cells and the human monocytic cell line THP-1. The cells were activated with silica, and IL-1beta release was determined using enzyme-linked immunosorbent assay or IL-1beta bioassays. The relative contribution of the active domain or integrin-binding domain of cathepsin Z was studied using recombinant cathepsin Z constructs and the alpha5 integrin neutralizing antibody. We report that the lysosomal cysteine protease cathepsin Z potentiates the development of inflammation associated with respiratory silicosis by augmenting NLRP3 inflammasome-derived IL-1beta expression in response to silica. The secreted cathepsin Z functions nonproteolytically via the internal integrin-binding domain to impact caspase-1 activation and the production of active IL-1beta through integrin alpha5 without affecting the transcription levels of NLRP3 inflammasome components. This work reveals a regulatory pathway for the NLRP3 inflammasome that occurs in an outside-in fashion and provides a link between extracellular cathepsin Z and inflammation. Furthermore, it reveals a level of NLRP3 inflammasome regulation that has previously only been found downstream of extracellular pathogens. |
