Think Beyond Particle Cytotoxicity: When Self-Cellular Components Released After Immunogenic Cell Death Explain Chronic Disease Development

Abstract

The prolonged perturbation of the immune system following the release of a plethora of self-molecules (known as damage-associated molecular patterns, DAMPs) by stressed or dying cells triggers acute and chronic pathological responses. DAMPs are commonly released after plasma membrane damage or complete rupture due to immunogenic cell death (ICD), upon numerous stressors including infectious and toxic agents. The set of DAMPs released after ICD include mature proinflammatory cytokines and alarmins, but also polymeric macromolecules. These self-intracellular components are recognized by injured and healthy surrounding cells via innate receptors, and induce upregulation of stress-response mechanisms, including inflammation. In this review, by overstepping the simple toxicological evaluation, we apply ICD and DAMP concepts to silica cytotoxicity, providing new insights on the mechanisms driving the progress and/or the exacerbation of certain SiO2–related pathologies. Finally, by proposing self-DNA as new crucial DAMP, we aim to pave the way for the development of innovative and easy-to-perform predictive tests to better identify the hazard of fine and ultrafine silica particles. Importantly, such mechanisms could be extended to nano/micro plastics and diesel particles, providing strategic advice and reports on their health issues.

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

“…After cellular insults, the release of self-intracellular components (known as damage-associated molecular patterns, DAMPs) activates innate and adaptive immunety and promotes pathological responses (Gong et al 2020 ). DAMPs are secreted via specific active mechanisms, or after plasma membrane disruption upon cell injury (Leinardi et al 2022 ). IL-1α is a paramount DAMP released in the extracellular environment and implicated in the production of cytokines and chemokines inducing monocyte and neutrophil influx in the injury site (Dinarello 2018 ).…”

Editorial: Exploring impacts of combined exposures to particles and chemicals on immune reactions across living organisms

“…Along with the danger theory ( Matzinger, 2002 ), the defensive inflammatory reaction can be initiated by exogenous PAMPs (pathogen-associated molecular patterns), or endogenous DAMPs (danger-associated molecular patterns), which activate an inflammatory reaction through innate receptors. Several types of nanoparticles, for instance crystalline silica, can kill immune cells, mostly assessed in in vitro models, by inducing membrane destabilisation and a chain of effects on organelle functions ( Pavan and Fubini, 2017 ; Leinardi et al, 2022 ). We should remember that silica has been used by immunologists since the 1950s for macrophage depletion.…”

“…The death of immune cells and in particular of the innate immune cells involved in a defensive reaction is critical to our immunity. Necrosis and immunogenic cell death (ICD), often triggered by the uptake of toxic particles by phagocytes ( Galluzzi et al, 2020 ; Leinardi et al, 2022 ), are an important source of DAMPs and a source of inflammatory and immunostimulatory cytokines, such as inflammasome-generated master cytokine IL-1β. The importance of IL-1β is well established for the initiation and maintenance of inflammation, particularly upon infection ( Dinarello, 2018 ) but also as part of the “fibre pathogenicity paradigm”: High aspect ratio particles can trigger IL-1β release from phagocytes similar to the known response to asbestos ( Palomäki et al, 2011 ).…”

“…Recent insights have confirmed and highlighted an important yet largely disregarded notion, i.e., that IL-1β has a role in decreasing and resolving inflammation ( Giesbrecht et al, 2017 ) and in tissue repair ( Choi et al, 2020 ), indicating that IL-1-initiated pathways are required for the rapid resolution of nanoparticle- ( Ganguly et al, 2009 ), and fibre-triggered lung inflammation ( Nikota et al, 2017 ). Persistent cell death, as observed upon inhalation of slowly cleared and highly cytotoxicity particles, such as quartz and certain rigid CNTs, will cause persistent release of alarmins and DAMPs, which will recruit more inflammatory leukocytes to the site of injury and thus eventually exacerbate the pathology ( Leinardi et al, 2022 ). Many DAMPs have been described, mainly nuclear and mitochondrial peptides and proteins such as N-formyl peptides, histones or HMGB1, and also nuclear and mitochondrial DNA, which is sensed as DAMP if released into the cytoplasm or extracellular space, thereby serving as an injury signal.…”

“…Inflammation caused by particles inhalation is generally a transient defensive reaction that declines with the elimination of the nanomaterial without causing serious damage to the organism ( Ganguly et al, 2009 ; Chen et al, 2016 ). It is only in a few cases, such as when the particles persist and cannot be eliminated, that the inflammatory reaction can become chronic and have pathological consequences ( Boraschi et al, 2017 ; Leinardi et al, 2022 ). The use of in vivo animal models or the evaluation of human exposure is therefore the most reliable ways of assessing particle toxicity despite the ethical challenges and the drive towards alternative approaches.…”