Long-term exposure to house dust mites accelerates lung cancer development in mice

Journal of Experimental & Clinical Cancer Research

Research

David Schwartz¹  Helen Snyder¹  Matt Levin¹  Zohreh AkhavanAghdam¹  Nissi Varki²  Nicholas J. G. Webster³  Bora Keum⁴  Hal M. Hoffman⁵  Laela M. Boosherhri⁵  Eyal Raz⁶  Han Chang⁶  Scott Herdman⁶  Samuel Bertin⁶  Lauren Amaya⁶  Lindsey Griffin⁶  Sneha Ganguly⁶  Maripat Corr⁶  Natalie Albasha⁶  Dongjie Wang⁷  Liping Zeng⁸  Wen Li⁸  José M. González-Navajas⁹  Ailin Tao^1,10  Monica Valeria Estrada^1,11  Michael Rose^1,11 

[1] Cell IDx Inc, San Diego, CA, USA;Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, USA;Division of Endocrinology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, USA;Medical Research Service, Veteran Affairs San Diego Healthcare System, San Diego, CA, USA;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea;Division of Pediatric Allergy, Immunology, and Rheumatology, Rady Children’s Hospital of San Diego, University of California San Diego, La Jolla, CA, USA;Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, 92093-0663, La Jolla, CA, USA;Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, 92093-0663, La Jolla, CA, USA;Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, 92093-0663, La Jolla, CA, USA;The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Center for Immunology, Inflammation and Immune-Mediated Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Hospital General Universitario de Alicante, Alicante, Spain;Alicante Institute of Health and Biomedical Research (ISABIAL), Alicante, Spain;The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Center for Immunology, Inflammation and Immune-Mediated Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;Tissue Technology Shared Resource, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA;

关键词: Lung cancer;    Kras;    Urethane;    House dust mites;    Chronic inflammation;    NLRP3;    IL-1β;    CCL2;    Macrophages;    Tumor microenvironment;   

DOI  :  10.1186/s13046-022-02587-9

 received in 2022-10-10, accepted in 2022-12-26,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundIndividuals 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). MethodsThe 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 KrasG12D 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. ResultsChronic 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.ConclusionsCollectively, 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).

【 授权许可】

CC BY   
© The Author(s) 2023. corrected publication 2023

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