Gasdermin D membrane pores orchestrate IL-1α secretion from necrotic macrophages after NFS-rich silica exposure

Abstract

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.

Cell circuits underlying nanomaterial specific respiratory toxicology

“…S3e ). Finally, this supports the hypothesis, that CNT phagocytosing tissue resident AMs undergo necrotic cell death, thereby releasing alarmins like IL1a, in a similar manner as described before for silica particles 24,25 .…”

Physico-Chemical Approaches to Investigate Surface Hydroxyls as Determinants of Molecular Initiating Events in Oxide Particle Toxicity

“…NFS are now held as the key molecular species that impart to respirable crystalline silica (RCS) the potency to induce cell membrane disruption, activate in vitro inflammatory responses, and trigger acute inflammation in the lungs of animals [1,42]. Mechanistically, NFS-rich but not NFS-poor silicas were proven to induce cytotoxicity in macrophages, leading to the secretion of alarmin IL-1α as one of the early inflammatory events triggered by silica particles [43]. A positive correlation between the presence of surface NFS and the membranolytic capacity of silica was proven for synthetic and natural quartz, amorphous silica [1,44], crystalline silica polymorphs [45], and crystalline nanosilica prepared by ball milling [46].…”