Long-term exposure to house dust mites accelerates lung cancer development in mice
Dongjie Wang, Wen Li, Natalie Albasha, Lindsey Griffin, Han Chang, Lauren Amaya, Sneha Ganguly, Liping Zeng, Bora Keum, José M. González‐Navajas, Matt Levin, Zohreh AkhavanAghdam, Helen Snyder, David A. Schwartz, Ailin Tao, Laela M. Boosherhri, Hal M. Hoffman, Michael Rose, Mónica V. Estrada, Nissi Varki, Scott Herdman, Maripat Corr, Nicholas J. G. Webster, Eyal Raz, Samuel Bertin
Abstract
Abstract Background Individuals with certain chronic inflammatory lung diseases have a higher risk of developing lung cancer (LC). However, the underlying mechanisms remain largely unknown. Here, we hypothesized that chronic exposure to house dust mites (HDM), a common indoor aeroallergen associated with the development of asthma, accelerates LC development through the induction of chronic lung inflammation (CLI). Methods The effects of HDM and heat-inactivated HDM (HI-HDM) extracts were evaluated in two preclinical mouse models of LC (a chemically-induced model using the carcinogen urethane and a genetically-driven model with oncogenic Kras G12D activation in lung epithelial cells) and on murine macrophages in vitro . Pharmacological blockade or genetic deletion of the Nod-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, caspase-1, interleukin-1β (IL-1β), and C–C motif chemokine ligand 2 (CCL2) or treatment with an inhaled corticosteroid (ICS) was used to uncover the pro-tumorigenic effect of HDM. Results Chronic intranasal (i.n) instillation of HDM accelerated LC development in the two mouse models. Mechanistically, HDM caused a particular subtype of CLI, in which the NLRP3/IL-1β signaling pathway is chronically activated in macrophages, and made the lung microenvironment conducive to tumor development. The tumor-promoting effect of HDM was significantly decreased by heat treatment of the HDM extract and was inhibited by NLRP3, IL-1β, and CCL2 neutralization, or ICS treatment. Conclusions Collectively, these data indicate that long-term exposure to HDM can accelerate lung tumorigenesis in susceptible hosts (e.g., mice and potentially humans exposed to lung carcinogens or genetically predisposed to develop LC).