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Early Life Represents a Vulnerable Time Window for IL-33–Induced Peripheral Lung Pathology

Li Y. Drake, Diane Squillace, Koji Iijima, Takao Kobayashi, Masaru Uchida, Gail M. Kephart, Rodney Britt, Daniel R. O'Brien and Hirohito Kita
J Immunol August 30, 2019, ji1900454; DOI: https://doi.org/10.4049/jimmunol.1900454
Li Y. Drake
*Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905;
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Diane Squillace
*Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905;
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Koji Iijima
*Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905;
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Takao Kobayashi
*Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905;
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Masaru Uchida
*Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905;
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Gail M. Kephart
*Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905;
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Rodney Britt
†Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905;
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Daniel R. O'Brien
‡Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905; and
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Hirohito Kita
§Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905
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Key Points

  • In adults, increased IL-33 expression in the lungs per se is not pathologic.

  • In neonates, increased IL-33 results in severe peripheral lung pathology.

  • Pathologic effects of IL-33 in the lungs are age dependent.

Abstract

IL-33, an IL-1 family cytokine, is constitutively expressed in mucosal tissues and other organs in healthy humans and animals, and expression levels increase in inflammatory conditions. Although IL-33–mediated promotion of type 2 immune responses has been well established, a gap in our knowledge regarding the functional diversity of this pleiotropic cytokine remains. To address this gap, we developed a new IL-33 transgenic mouse model in which overexpression of full-length IL-33 is induced in lung epithelial cells under conditional control. In adult mice, an ∼3-fold increase in the steady-state IL-33 levels produced no pathologic effects in the lungs. When exposed to airborne allergens, adult transgenic mice released more IL-33 extracellularly and exhibited robust type 2 immune responses. In neonatal transgenic mice, up to postnatal day 14, a similar increase in steady-state IL-33 levels resulted in increased mortality, enlarged alveolar spaces resembling bronchopulmonary dysplasia, and altered expression of genes associated with tissue morphogenesis. Processed 25-kDa IL-33 protein was detected in bronchoalveolar lavage fluids without any exogenous stimuli, and pathologic changes were abolished in mice deficient in the IL-33 receptor ST2. These findings suggest that adult lungs are relatively resistant to IL-33 overexpression unless they encounter environmental insults, whereas developing lungs are highly susceptible, with IL-33 overexpression resulting in detrimental and pathologic outcomes.

Footnotes

  • This work was supported by grants from the National Institutes of Health (R01 AI128729) and the Mayo Foundation.

  • The sequencing data presented in this article have been submitted to the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number SRP198258.

  • The online version of this article contains supplemental material.

  • Received April 22, 2019.
  • Accepted July 29, 2019.
  • Copyright © 2019 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (2)
The Journal of Immunology
Vol. 206, Issue 2
15 Jan 2021
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Early Life Represents a Vulnerable Time Window for IL-33–Induced Peripheral Lung Pathology
Li Y. Drake, Diane Squillace, Koji Iijima, Takao Kobayashi, Masaru Uchida, Gail M. Kephart, Rodney Britt, Daniel R. O'Brien, Hirohito Kita
The Journal of Immunology August 30, 2019, ji1900454; DOI: 10.4049/jimmunol.1900454

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Early Life Represents a Vulnerable Time Window for IL-33–Induced Peripheral Lung Pathology
Li Y. Drake, Diane Squillace, Koji Iijima, Takao Kobayashi, Masaru Uchida, Gail M. Kephart, Rodney Britt, Daniel R. O'Brien, Hirohito Kita
The Journal of Immunology August 30, 2019, ji1900454; DOI: 10.4049/jimmunol.1900454
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Print ISSN 0022-1767        Online ISSN 1550-6606