Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema
- Baylor College of Medicine, United States
- City of Hope National Medical Center, United States
- Rice University, United States
Abstract
Chronic inhalation of cigarette smoke is the major cause of sterile inflammation and pulmonary emphysema. The effect of carbon black (CB), a universal constituent of smoke derived from the incomplete combustion of organic material, in smokers and non-smokers is less known. Here we show that insoluble nanoparticulate carbon black (nCB) accumulates in human myeloid dendritic cells (mDCs) from emphysematous lung and in CD11c+ lung antigen presenting cells (APC) of mice exposed to smoke. Likewise, nCB intranasal administration induced emphysema in mouse lungs. Delivered by smoking or intranasally, nCB persisted indefinitely in mouse lung, activated lung APCs, and promoted T helper 17 cell differentiation through double-stranded DNA break (DSB) and ASC-mediated inflammasome assembly in phagocytes. Increasing the polarity or size of CB mitigated many adverse effects. Thus, nCB causes sterile inflammation, DSB, and emphysema, and explains adverse health outcomes seen in smokers while implicating the dangers of nCB exposure in non-smokers.
Article and author information
Author details
Reviewing Editor
- Feng Shao, National Institute of Biological Sciences, China
Ethics
Animal experimentation: C57BL/6J mice were purchased from the Jackson Laboratory. ASC-/- mice (C57BL/6 background) were obtained from Dr. Vishva Dixit (Genentech, South San Francisco, CA). IL-17A-/- mice (C57BL/6 background) were obtained from Dr. Chen Dong (The University of Texas MD Anderson Cancer Center, Houston, TX). All mice were bred in the transgenic animal facility at Baylor College of Medicine. All experimental protocols(AN-4589) used in this study were approved by the Institutional Animal Care and Use Committee of Baylor College of Medicine and followed the National Research Council Guide for the Care and Use of Laboratory Animals.
Version history
- Received: June 23, 2015
- Accepted: September 15, 2015
- Accepted Manuscript published: October 5, 2015 (version 1)
- Version of Record published: October 21, 2015 (version 2)
Copyright
© 2015, You et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema
eLife 4:e09623.
https://doi.org/10.7554/eLife.09623
Further reading
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The elemental carbon in cigarette smoke causes inflammation and emphysema in the lung.
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- Immunology and Inflammation
Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 microRNA (Mirlet7 miRNA) family is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the Mirlet7 family is downregulated in patients with COPD, however, whether this repression conveys a functional consequence on emphysema pathology has not been elucidated. Here, we show that overall expression of the Mirlet7 clusters, Mirlet7b/Mirlet7c2 and Mirlet7a1/Mirlet7f1/Mirlet7d, are reduced in the lungs and T cells of smokers with emphysema as well as in mice with cigarette smoke (CS)- or nCB-elicited emphysema. We demonstrate that loss of the Mirlet7b/Mirlet7c2 cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of the Mirlet7b/Mirlet7c2 cluster enhanced CD8+IL17a+ T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressing Mirlet7g in T cells are resistant to Tc17 and CD4+IL17a+ T cells (Th17) development when exposed to nCB. Mechanistically, our findings reveal the master regulator of Tc17/Th17 differentiation, RAR-related orphan receptor gamma t (RORγt), as a direct target of Mirlet7 in T cells. Overall, our findings shed light on the Mirlet7/RORγt axis with Mirlet7 acting as a molecular brake in the generation of Tc17 cells and suggest a novel therapeutic approach for tempering the augmented IL-17-mediated response in emphysema.
