Hypoxia contributes to airway inflammation and remodeling in several lung diseases; however, exactly how hypoxic pulmonary epithelium regulates allergic inflammation remains to be fully characterized. Here, we report that conditional deletion of the E3 ubiquitin ligase VHL in lung epithelial cells resulted in exacerbated type 2 responses accompanied by selective increase of group 2 innate lymphoid cells (ILC2s) at steady state and following inflammation or helminth infection. Ablation of expression of the hypoxia-inducible factor 2α (HIF2α) significantly reversed VHL-mediated ILC2 activation. VHL deficiency in lung epithelial cells caused increased expression of the peptide hormone adrenomedullin (ADM), and our data suggest that HIF2α controls Adm expression. ADM directly promoted ILC2 activation both in vitro and in vivo. Our findings indicate that the hypoxic response mediated by the VHL–HIF2α axis is critical for control of pulmonary type 2 responses by increasing ADM expression in lung epithelia, causing ILC2 activation.
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6 June 2022
Article|
May 09 2022
Hypoxia induces adrenomedullin from lung epithelia, stimulating ILC2 inflammation and immunity
Jihye Han
,
(Conceptualization, Data curation, Formal analysis, Investigation, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
La Jolla Institute for Immunology, La Jolla, CA
Jihye Han: jhan@lji.org
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Qingqing Wan
,
Qingqing Wan
(Data curation, Formal analysis, Methodology)
1
La Jolla Institute for Immunology, La Jolla, CA
3
Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China
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Goo-Young Seo
,
Goo-Young Seo
(Investigation, Methodology, Resources, Visualization, Writing - review & editing)
1
La Jolla Institute for Immunology, La Jolla, CA
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Kenneth Kim
,
Kenneth Kim
(Investigation, Visualization, Writing - review & editing)
1
La Jolla Institute for Immunology, La Jolla, CA
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Sarah el Baghdady
,
Sarah el Baghdady
(Investigation, Methodology, Project administration)
1
La Jolla Institute for Immunology, La Jolla, CA
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Jee H. Lee
,
Jee H. Lee
(Methodology, Resources, Writing - review & editing)
1
La Jolla Institute for Immunology, La Jolla, CA
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Mitchell Kronenberg
,
(Conceptualization, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - review & editing)
1
La Jolla Institute for Immunology, La Jolla, CA
2
Division of Biological Sciences, University of California San Diego, La Jolla, CA
Correspondence to Mitchell Kronenberg: mitch@lji.org
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Yun-Cai Liu
(Conceptualization, Funding acquisition, Project administration, Supervision, Writing - review & editing)
1
La Jolla Institute for Immunology, La Jolla, CA
3
Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China
Yun-Cai Liu: yuncail@hotmail.com
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Jihye Han
Conceptualization, Data curation, Formal analysis, Investigation, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing
1
La Jolla Institute for Immunology, La Jolla, CA
Qingqing Wan
Data curation, Formal analysis, Methodology
1
La Jolla Institute for Immunology, La Jolla, CA
3
Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China
Goo-Young Seo
Investigation, Methodology, Resources, Visualization, Writing - review & editing
1
La Jolla Institute for Immunology, La Jolla, CA
Kenneth Kim
Investigation, Visualization, Writing - review & editing
1
La Jolla Institute for Immunology, La Jolla, CA
Sarah el Baghdady
Investigation, Methodology, Project administration
1
La Jolla Institute for Immunology, La Jolla, CA
Jee H. Lee
Methodology, Resources, Writing - review & editing
1
La Jolla Institute for Immunology, La Jolla, CA
Mitchell Kronenberg
Conceptualization, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - review & editing
1
La Jolla Institute for Immunology, La Jolla, CA
2
Division of Biological Sciences, University of California San Diego, La Jolla, CA
Correspondence to Mitchell Kronenberg: mitch@lji.org
Yun-Cai Liu: yuncail@hotmail.com
Jihye Han: jhan@lji.org
The authors declare no competing financial interests.
Received:
September 21 2021
Revision Received:
February 21 2022
Accepted:
April 04 2022
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding
Funder(s):
National Institutes of Health
- Award Id(s): S10RR027366,R01AI123398,U01 AI125955
© 2022 Han et al.
2022
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2022) 219 (6): e20211985.
Article history
Received:
September 21 2021
Revision Received:
February 21 2022
Accepted:
April 04 2022
Citation
Jihye Han, Qingqing Wan, Goo-Young Seo, Kenneth Kim, Sarah el Baghdady, Jee H. Lee, Mitchell Kronenberg, Yun-Cai Liu; Hypoxia induces adrenomedullin from lung epithelia, stimulating ILC2 inflammation and immunity. J Exp Med 6 June 2022; 219 (6): e20211985. doi: https://doi.org/10.1084/jem.20211985
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