Mast cells and the IL-33/ST2 axis are essential determinants of carbon nanotube toxicity

Abstract

The rise of nanomaterial use in a variety of applications, including biomedical imaging and drug delivery, has led to concern about the potentially hazardous impacts on human health. Mast cells are critical for innate and adaptive immune responses, often modulating allergic and pathogenic conditions, including pulmonary and cardiovascular diseases. Mast cells are well known to act in response to danger signals through a variety of receptors and pathways including IL-33 and the IL-1 like receptor ST2. The aim of this study was to investigate involvement of mast cells and the IL-33/ST2 axis in the pulmonary and cardiovascular toxicities induced by engineered multi-walled carbon nanotubes (MWCNTs) following oropharyngeal aspiration. We assessed inflammatory, fibrotic, and functional responses in the lung, as well as cardiac ischemia-reperfusion (IR) injury responses in C57BL/6, Kit W-sh (mast cell deficient), Kit W-sh reconstituted with either wild-type or ST2 mast cells, and ST2 deficient mice. Mice with a sufficient population of mast cells (C57BL/6 and reconstituted Kit W-sh mice) exhibited significant pulmonary inflammation, exhibited by increased neutrophils and associated with elevated IL-33, impaired pulmonary function, increased granuloma formation, and collagen deposition 30 days following exposure to MWCNT. Additionally, exacerbation of myocardial infarction was observed in the same groups of mice 1 day following MWCNT exposure. These toxicological effects of MWCNTs were observed only in mice with a sufficient population of mast cells and were not observed when mast cells were absent or incapable of responding to IL-33 (Kit W-sh, Kit W-sh reconstituted with ST2 mast cells or ST2 mice). These findings establish for the first time, an unrecognized, but critical role for mast cells and the IL-33/ST2 axis in orchestrating adverse pulmonary and cardiovascular responses to an engineered nanomaterial, giving insight into a previously unknown mechanism of toxicity. In identifying the importance of the IL-33/ST2 axis and mast cells in this novel mechanism of toxicity, our study provides a means of addressing current concerns regarding nanoparticle exposures and the safety of engineered nanomaterials for use in biomedical applications in identifying a realistic therapeutic target for potential nanoparticle induced toxicities.