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ResearchIn-Press PreviewInfectious diseasePulmonology Open Access | 10.1172/jci.insight.166608

Impaired PPARɣ activation by cadmium exacerbates infection-induced lung injury

Jennifer L. Larson-Casey,1 Shanrun Liu,2 Jennifer M. Pyles,3 Suzanne E. Lapi,3 Komal Saleem,1 Veena B. Antony,1 Manuel Lora Gonzalez,4 David K. Crossman,5 and A. Brent Carter1

1Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

2Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Radiology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

5Department of Genetics, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Larson-Casey, J. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

2Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Radiology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

5Department of Genetics, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Liu, S. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

2Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Radiology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

5Department of Genetics, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Pyles, J. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

2Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Radiology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

5Department of Genetics, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Lapi, S. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

2Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Radiology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

5Department of Genetics, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Saleem, K. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

2Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Radiology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

5Department of Genetics, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Antony, V. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

2Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Radiology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

5Department of Genetics, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Gonzalez, M. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

2Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Radiology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

5Department of Genetics, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Crossman, D. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

2Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Radiology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

5Department of Genetics, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Carter, A. in: JCI | PubMed | Google Scholar |

Published March 16, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.166608.
Copyright © 2023, Larson-Casey et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 16, 2023 - Version history
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Abstract

Emerging data indicates an association between environmental heavy metal exposure and lung disease, including lower respiratory tract infections (LRTIs). Here, we show by single cell RNA-sequencing an increase in Pparg gene expression in lung macrophages from mice exposed to cadmium and/or infected with S. pneumoniae. However, the heavy metal cadmium or infection mediated an inhibitory post-translational modification of peroxisome proliferator-activated receptor ɣ (PPARɣ) to exacerbate LRTIs. Cadmium and infection increased ERK activation to regulate PPARɣ degradation in monocyte-derived macrophages. Mice harboring a conditional deletion of Pparg in monocyte-derived macrophages had more severe S. pneumoniae infection after cadmium exposure, showed greater lung injury, and had increased mortality. Inhibition of ERK activation with BVD-523 protected mice from lung injury after cadmium exposure or infection. Moreover, subjects residing in areas of high air cadmium levels had increased cadmium concentration in their BAL fluid, increased barrier dysfunction, and showed PPARɣ inhibition that was mediated, at least in part, by ERK activation in isolated BAL cells. These observations suggest that impaired activation of PPARɣ in monocyte-derived macrophages exacerbates lung injury and the severity of LRTIs.

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