Endocytosis of indium-tin-oxide nanoparticles by macrophages provokes pyroptosis requiring NLRP3-ASC-Caspase1 axis that can be prevented by mesenchymal stem cells

Abstract

The biological effects of indium-tin-oxide (ITO) are of considerable importance because workers exposed to indium compounds have been diagnosed with interstitial lung disease or pulmonary alveolar proteinosis; however, the pathophysiology of these diseases is undefined. Here, mice intraperitoneally inoculated with ITO-nanoparticles (ITO-NPs) resulted in peritonitis dependent in NLRP3 inflammasome, with neutrophils recruitment and interleukin-1β (IL-1β) production. Withal peritoneal macrophages exposed ex vivo to ITO-NPs caused IL-1β secretion and cytolysis. Further, alveolar macrophages exposed to ITO-NPs in vitro showed ITO-NP endocytosis and production of tumor necrosis factor-α (TNF-α) and IL-1β, ensued cell death by cytolysis. This cell death was RIPK1-independent but caspase1-dependent, and thus identified as pyroptosis. Endocytosis of ITO-NPs by activated THP-1 cells induced pyroptosis with IL-1β/TNF-α production and cytolysis, but not in activated THP-1 cells with knockdown of NLRP3, ASC, or caspase1. However, exposing activated THP-1 cells with NLRP3 or ASC knockdown to ITO-NPs resulted in cell death but without cytolysis, with deficiency in IL-1β/TNF-α, and revealing features of apoptosis. While, mesenchymal stem cells (MSCs) co-cultured with macrophages impaired both inflammation and cell death induced by ITO-NPs. Together, our findings provide crucial insights to the pathophysiology of respiratory diseases caused by ITO particles, and identify MSCs as a potent therapeutic.

Cytokine Profiling of Primary Human Macrophages Exposed to Endotoxin‐Free Graphene Oxide: Size‐Independent NLRP3 Inflammasome Activation

“…THP‐1 Knockdown Cell Lines : Four different THP‐1 monocytic cell lines (Null‐1, defASC, defNLRP3, and defCaspase‐1) were obtained from InvivoGen (France). The THP‐1 null and knockdown cells were cultured according to the manufacturers' instructions. After sub‐culturing the cells thrice in RPMI‐1640 cell medium supplemented with 10% FBS, cells were seeded in 96‐well plates at a density of 10 5 cells per well.…”

The toxicology of indium tin oxide

“…This cell death was RIPK1-independent but caspase1-dependent, and thus identified as pyroptosis. The authors speculated that the pyroptosis induced by ITO-NPs in macrophages may be a mechanism of exacerbated inflammation in the lungs after inhalation (Naji et al, 2016).…”

Rationale for Determining the Functional Potency of Mesenchymal Stem Cells in Preventing Regulated Cell Death for Therapeutic Use

“…Emerging studies suggest that MSCs can inhibit RCD such as necroptosis [], and we recently showed that MSCs could prevent pyroptosis in macrophages []. We focused on the pathogenesis of severe occupational lung diseases such as interstitial lung disease and pulmonary alveolar proteinosis, which could involve pyroptosis of lung macrophages caused by inhalation of inorganic particles []. This pyroptosis is characterized by the production of inflammatory cytokines and cell death by cytolysis, events depending on the inflammasome NACHT, LRR, and PYD domain‐containing protein 3–apoptosis‐associated speck‐like protein containing a CARD–Caspase‐1 (NLRP3‐ASC‐Caspase‐1) [].…”

“…Features of RCD and ACD with the role of MSCs in preventing RCD in terminally differentiated third-party cells Data are based mostly on the studies reported in[22,23,33,34,[43][44][45][46]. Additional citations can be found throughout the article.The plasma membrane of cells undergoing apoptosis remains intact but not with efferocytosis failure, during which cells might progress to secondary necrosis.…”