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The Innate Lymphoid System Is a Critical Player in the Manifestation of Mucoinflammatory Airway Disease in Mice

Brandon W. Lewis, Ishita Choudhary, Kshitiz Paudel, Yun Mao, Rahul Sharma, Yong Wang, Jessy S. Deshane, Richard C. Boucher, Sonika Patial and Yogesh Saini
J Immunol August 17, 2020, ji2000530; DOI: https://doi.org/10.4049/jimmunol.2000530
Brandon W. Lewis
*Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803;
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Ishita Choudhary
*Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803;
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Kshitiz Paudel
*Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803;
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Yun Mao
*Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803;
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Rahul Sharma
†National Hansen’s Disease Program, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803;
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Yong Wang
‡Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; and
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Jessy S. Deshane
‡Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; and
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Richard C. Boucher
§Marsico Lung Institute/University of North Carolina Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
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Sonika Patial
*Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803;
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Yogesh Saini
*Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803;
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Key Points

  • The innate lymphoid system promotes bacterial clearance from airspaces.

  • The innate lymphoid system mediates Th2 responses in the Tg+ airspaces.

  • Ablation of the innate lymphoid system abolishes MCM in the Tg+ airspaces.

Abstract

Innate lymphoid and adaptive immune cells are known to regulate epithelial responses, including mucous cell metaplasia (MCM), but their roles in mucoinflammatory airway diseases, such as cystic fibrosis, remain unknown. Scnn1b transgenic (Scnn1b-Tg+) mice, which recapitulate cystic fibrosis–like mucoinflammatory airway disease, deficient in innate lymphoid (Il2rg knockout mice [Il2rgKO]), adaptive immune (Rag1 knockout mice [Rag1KO]), or both systems (Il2rgKO/Rag1KO), were employed to investigate their respective contributions in the pathogenesis of mucoinflammatory airway disease. As previously reported, immunocompetent Tg+ juveniles exhibited spontaneous neonatal bacterial infections with robust mucoinflammatory features, including elevated expression of Th2-associated markers accompanied by MCM, elevated MUC5B expression, and airway mucus obstruction. The bacterial burden was increased in Il2rgKO/Tg+ juveniles but returned to significantly lower levels in Il2rgKO/Rag1KO/Tg+ juveniles. Mechanistically, this improvement reflected reduced production of adaptive immunity-derived IL-10 and, in turn, increased activation of macrophages. Although all the mucoinflammatory features were comparable between the immunocompetent Tg+ and Rag1KO/Tg+ juveniles, the Il2rgKO/Tg+ and Il2rgKO/Rag1KO/Tg+ juveniles exhibited suppressed expression levels of Th2 markers, diminished MCM, suppressed MUC5B expression, and reduced mucus obstruction. Collectively, these data indicate that, in the context of airway mucus obstruction, the adaptive immune system suppresses antibacterial macrophage activation, whereas the innate lymphoid system contributes to MCM, mucin production, and mucus obstruction.

Footnotes

  • This work was supported by National Institute of General Medical Sciences Grants 5P30GM110760 (Pilot Project Funding) and P20GM130555-6611 (to Y.S.) and National Institute of Environmental Health Sciences Grant R01ES030125 (to Y.S.).

  • The online version of this article contains supplemental material.

  • Received May 12, 2020.
  • Accepted July 21, 2020.
  • Copyright © 2020 by The American Association of Immunologists, Inc.

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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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The Innate Lymphoid System Is a Critical Player in the Manifestation of Mucoinflammatory Airway Disease in Mice
Brandon W. Lewis, Ishita Choudhary, Kshitiz Paudel, Yun Mao, Rahul Sharma, Yong Wang, Jessy S. Deshane, Richard C. Boucher, Sonika Patial, Yogesh Saini
The Journal of Immunology August 17, 2020, ji2000530; DOI: 10.4049/jimmunol.2000530

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The Innate Lymphoid System Is a Critical Player in the Manifestation of Mucoinflammatory Airway Disease in Mice
Brandon W. Lewis, Ishita Choudhary, Kshitiz Paudel, Yun Mao, Rahul Sharma, Yong Wang, Jessy S. Deshane, Richard C. Boucher, Sonika Patial, Yogesh Saini
The Journal of Immunology August 17, 2020, ji2000530; DOI: 10.4049/jimmunol.2000530
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Print ISSN 0022-1767        Online ISSN 1550-6606