Extracellular cathepsin Z signals through the α5 integrin and augments NLRP3 inflammasome activation

• Published in: The Journal of biological chemistry 2022-01, Vol.298 (1), p.101459-101459, Article 101459
• Main Authors: Campden, Rhiannon I., Warren, Amy L., Greene, Catherine J., Chiriboga, Jose A., Arnold, Corey R., Aggarwal, Devin, McKenna, Neil, Sandall, Christina F., MacDonald, Justin A., Yates, Robin M.
• Format: Article
• Language: English
• Subjects: arginine-glycine-aspartic acid (RGD) domain; cathepsin Z; inflammasome; inflammation; integrin; interleukin-1 (IL-1); NLRP3; silica; silicosis
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2021.101459

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-1β production. Cathepsin Z has been associated with the development of inflammation and IL-1β production; however, the mechanism of how cathepsin Z leads to IL-1β 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-1β release was determined using enzyme-linked immunosorbent assay or IL-1β bioassays. The relative contribution of the active domain or integrin-binding domain of cathepsin Z was studied using recombinant cathepsin Z constructs and the α5 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-1β 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-1β through integrin α5 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.