The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter

• Published in: Journal of allergy and clinical immunology Vol. 129; no. 4; pp. 1116 - 1125.e6
• Main Authors: Hirota, Jeremy A., PhD, Hirota, Simon A., PhD, Warner, Stephanie M., BSc, Stefanowicz, Dorota, BSc, Shaheen, Furquan, BSc, Beck, Paul L., MD, PhD, MacDonald, Justin A., PhD, Hackett, Tillie-Louise, PhD, Sin, Don D., MD, Van Eeden, Stephan, MD, Knight, Darryl A., PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.04.2012; Elsevier; Elsevier Limited
• Subjects: Allergy and Immunology; Animals; Asthma; Biological and medical sciences; Bronchus; Carrier Proteins - metabolism; Caspase-1; Cell culture; Cell growth; Cell number; Cloning; Cytokines; Dehydrogenases; dendritic cell; Dendritic Cells - immunology; Dendritic Cells - metabolism; Epithelium; Experiments; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; human; Humans; Hypotheses; IL-1β; Immune response; Immune system; Immunopathology; Immunophenotyping; Inflammasomes - metabolism; Inflammation; Interleukin 1; Interleukin-1beta - metabolism; Lung diseases; Lymph nodes; Major histocompatibility complex; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; mouse; Neutrophilia; NLR Family, Pyrin Domain-Containing 3 Protein; Nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome; oxidative stress; Particulate matter; Particulate Matter - immunology; particulate matter with mean diameter less than 10 μm; Protein expression; Protein Transport; Proteins; Proteins - genetics; Proteins - metabolism; Respiratory Mucosa - immunology; Respiratory Mucosa - metabolism; Respiratory tract; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Studies; EHC; PM 10; Small interfering RNA; siRNA; IL-1β; Environmental Health Canada; BAL; Wild-type; mouse; Bronchoalveolar lavage; Nucleotide-binding domain and leucine-rich repeat protein 3; BEGM; Particulate matter; Nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome; NLRP3; Bronchial epithelial growth medium; human; PM; WT; particulate matter with mean diameter less than 10 μm; oxidative stress; dendritic cell; PM10; Oxidative stress; Binding site; Respiratory system; Particle; Respiratory tract; Immunology; Antigen presenting cell; Diameter; Human; Dendritic cell; Immunopathology; Urban environment; Cytokine; Rodentia; Interleukin 1β; Epithelium; Protein; Vertebrata; Mammalia; Mouse; Leucine-rich repeat region; Animal; Nucleotide
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2011.11.033

Background The airway epithelium is the first line of defense against inhaled insults and therefore must be capable of coordinating appropriate inflammatory and immune responses. Objective We sought to test the hypothesis that the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, an intracellular danger-sensing complex, plays a critical role in airway epithelium–mediated immune responses to urban particulate matter (PM) exposure. Methods In this study we (1) identified NLRP3 and caspase-1 expression in human airway epithelium bronchus and primary cells, (2) characterized NLRP3 inflammasome–mediated IL-1β production from human airway epithelium in response to PM, and (3) performed in vivo PM exposure experiments with wild-type and Nlrp3−/− mice. Results Our results demonstrate that human airway epithelium contains a functional NLRP3 inflammasome that responds to PM exposure with caspase-1 cleavage and production of IL-1β. Exposure of Nlrp3−/− and wild-type mice to PM in vivo demonstrates NLRP3-dependent production of IL-1β in the lung, airway neutrophilia, and increases in CD11c+hi /MHC class II+hi cell numbers in intrathoracic lymph nodes. Conclusion Our study is the first to characterize airway epithelial NLRP3 inflammasome–mediated immune responses to PM exposure, which might have implications in patients with asthma and other lung diseases.