Journal
TOXICOLOGICAL SCIENCES
Volume 170, Issue 2, Pages 462-475Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfz099
Keywords
asthma; toluene diisocyanate; neutrophilic inflammation; caspase-1; NLRP3
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Funding
- National Key R&D Program of China [2017YFC1310601]
- National Natural Science Foundation of China [81871266, 81800022]
- Natural Science Foundation of Guangdong Province [2018A0303130244]
- Guangzhou Healthcare Collaborative Innovation Major Project [201604020012]
- Scientific and Technological Project of Guangzhou [201804020042, 201707010026]
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Multiple studies have addressed the vital role of Nod-like receptor protein 3(NLRP3)/caspase-1/IL-1 beta signaling in asthma. Yet, the role of NLRP3/caspase-1 in toluene diisocyanate (TDI)-induced asthma is still obscure. The aim of this study is to investigate the role of the NLRP3/caspase-1 axis in TDI-induced asthma. Using an established murine model of TDI-induced asthma as described previously, we gave the asthmatic mice a highly selective NLRP3 inhibitor, MCC950, as well as the specific caspase-1 inhibitors VX-765 and Ac-YVAD-CHO for therapeutic purposes. Airway resistance was measured and bronchoalveolar lavage fluid was analyzed. Lungs were examined by histology, immunohistochemistry, Western blotting, and flow cytometry. TDI exposure elevated the expression of NLRP3 and caspase-1 that was coupled with increased airway hyperresponsiveness (AHR), neutrophil-dominated cell infiltration, pronounced goblet cell metaplasia, extensive collagen deposition, and increased T(H)2/T(H)17 responses. Both VX-765 and Ac-YVAD-CHO effectively inhibited the activation of caspase-1 in TDI-asthmatic mice that was accompanied by dramatic attenuation of AHR, airway inflammation, and airway remodeling, in addition to a decreased T(H)2 response and lower levels of IL-18 and IL-1 beta. MCC950 blocked the activation of NLRP3 and downregulated protein expression of caspase-1, IL-1 beta, and IL-18 in TDI-exposed mice. Furthermore, MCC950 remarkably alleviated AHR, airway inflammation, airway remodeling, and significantly suppressed T(H)2/T(H)17 responses. These findings suggested that blockade of the NLRP3/caspase-1 axis effectively prevents the progression of TDI-induced asthma and could be used as therapeutic targets for asthmatics.
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