Extracellular cathepsin Z signals through the α5 integrin and augments NLRP3 inflammasome activation
| Autor: | Justin A. MacDonald, Catherine J. Greene, Christina F. Sandall, Neil McKenna, Rhiannon I. Campden, Jose A. Chiriboga, Robin M. Yates, Devin Aggarwal, Amy L. Warren, Corey R. Arnold |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Inflammasomes
Interleukin-1beta Integrin alpha5 Biochemistry Mice 0302 clinical medicine 0303 health sciences biology Chemistry interleukin-1 (IL-1) Inflammasome Silicon Dioxide PMA phorbol myristate acetate Cysteine protease 3. Good health Cell biology silica LPS lipopolysaccharide medicine.symptom RGD arginine-glycine-asparigine Research Article medicine.drug integrin Silicosis Integrin Inflammation MSU monosodium urate MS multiple sclerosis EAE encephalomyelitis 03 medical and health sciences NLRP3 FBS fetal bovine serum inflammasome NLR Family Pyrin Domain-Containing 3 Protein medicine Extracellular Animals APC antigen-presenting cells Molecular Biology BMDC bone marrow-derived dendritic cells 030304 developmental biology Cathepsin Cathepsin Z Cell Biology arginine-glycine-aspartic acid (RGD) domain Cell culture biology.protein 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.101459 |
| Popis: | 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 wildtype mice and mice deficient in cathepsin Z. The activation of the NLRP3 inflammasome in macrophages was studied using wildtype and cathepsin Z-deficient bone marrow-derived murine dendritic cells and the human monocytic cell line THP-1. 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. Secreted cathepsin Z functions non-proteolytically via the internal integrin-binding domain to impact caspase-1 activation and the production of active IL-1β through integrin α5 without affecting 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|