Injury-induced pulmonary tuft cells are heterogenous, arise independent of key Type 2 cytokines, and are dispensable for dysplastic repair
- University of California, San Diego, United States
- University of Pennsylvania, United States
- University of California, San Francisco, United States
- University of Washington, United States
- Monell Chemical Senses Center, United States
Abstract
While the lung bears significant regenerative capacity, severe viral pneumonia can chronically impair lung function by triggering dysplastic remodeling. The connection between these enduring changes and chronic disease remains poorly understood. We recently described the emergence of tuft cells within Krt5+ dysplastic regions after influenza injury. Using bulk and single cell transcriptomics, we characterized and delineated multiple distinct tuft cell populations that arise following influenza clearance. Distinct from intestinal tuft cells which rely on Type 2 immune signals for their expansion, neither IL-25 nor IL-4ra signaling are required to drive tuft cell development in dysplastic/injured lungs. In addition, tuft cell expansion occurred independently of type I or type III interferon signalling. Furthermore, tuft cells were also observed upon bleomycin injury, suggesting that their development may be a general response to severe lung injury. While intestinal tuft cells promote growth and differentiation of surrounding epithelial cells, in the lungs of tuft cell deficient mice, Krt5+ dysplasia still occurs, goblet cell production is unchanged, and there remains no appreciable contribution of Krt5+ cells into more regionally appropriate alveolar Type 2 cells. Together, these findings highlight unexpected differences in signals necessary for murine lung tuft cell amplification and establish a framework for future elucidation of tuft cell functions in pulmonary health and disease.
Data availability
Sequencing data have been deposited in GEO under accession code GSE197163.In addition to the deposited sequencing data, raw numerical data is available as excel files corresponding to each figure, e.g. Figure 1 - Source Data.xls.
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Author details
Funding
National Institutes of Health (R01HL153539)
- Andrew E Vaughan
U.S. Department of Veterans Affairs (CX001617)
- Noam A Cohen
Fonds de Recherche du Québec - Santé
- Maria Elena Gentile
Lisa Dean Moseley Foundation
- Andrew E Vaughan
National Institutes of Health (R01HL142215)
- Xin Sun
National Institutes of Health (1R01AT011676)
- Xin Sun
National Institutes of Health (T29IR0475)
- Xin Sun
National Institutes of Health (F32HL151168)
- Justinn Barr
National Institutes of Health (F32HL140868)
- Maya E Kotas
National Institutes of Health (T32HL007185)
- Maya E Kotas
A.P. Giannini Foundation
- Maya E Kotas
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Pennsylvania, the University of California - San Diego, and the University of California, San Francisco. All experiments were performed with every effort to minimize suffering. The protocol number associated with the ethical approval of this work is 806262 (University of Pennsylvania) and S16187 (University of California San Diego).
Copyright
© 2022, Barr 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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Injury-induced pulmonary tuft cells are heterogenous, arise independent of key Type 2 cytokines, and are dispensable for dysplastic repair
eLife 11:e78074.
https://doi.org/10.7554/eLife.78074
