| Autor: |
Riccardo Leinardi, Amandine Pochet, Francine Uwambayinema, Yousof Yakoub, Valérie Quesniaux, Bernhard Ryffel, Petr Broz, Cristina Pavan, François Huaux |
| Přispěvatelé: |
UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Archives of toxicology, Vol. 97, no. 4, p. 1001-1015 (2023) |
| Popis: |
IL-1α is an intracellular danger signal (DAMP) released by macrophages contributing to the development of silica-induced lung inflammation. The exact molecular mechanism orchestrating IL-1α extracellular release from particle-exposed macrophages is still unclear. To delineate this process, murine J774 and bone-marrow derived macrophages were exposed to increasing concentrations (1–40 cm2/ml) of a set of amorphous and crystalline silica particles with different surface chemical features. In particular, these characteristics include the content of nearly free silanols (NFS), a silanol population responsible for silica cytotoxicity recently identified. We first observed de novo stocks of IL-1α in macrophages after silica internalization regardless of particle physico-chemical characteristics and cell stress. IL-1α intracellular production and accumulation were observed by exposing macrophages to biologically-inert or cytotoxic crystalline and amorphous silicas. In contrast, only NFS-rich reactive silica particles triggered IL-1α release into the extracellular milieu from necrotic macrophages. We demonstrate that IL-1α is actively secreted through the formation of gasdermin D (GSDMD) pores in the plasma membrane and not passively released after macrophage plasma membrane lysis. Our findings indicate that the GSDMD pore-dependent secretion of IL-1α stock from macrophages solely depends on cytotoxicity induced by NFS-rich silica. This new regulated process represents a key first event in the mechanism of silica toxicity, suitable to refine the existing adverse outcome pathway (AOP) for predicting the inflammatory activity of silicas. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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