Injury-induced pulmonary tuft cells are heterogenous, arise independent of key Type 2 cytokines, and are dispensable for dysplastic repair

  1. Justinn Barr
  2. Maria Elena Gentile
  3. Sunyoung Lee
  4. Maya E Kotas
  5. Maria Fernanda de Mello Costa
  6. Nicolas P Holcomb
  7. Abigail Jaquish
  8. Gargi Palashikar
  9. Marcella Soewignjo
  10. Margaret McDaniel
  11. Ichiro Matsumoto
  12. Robert Margolskee
  13. Jakob Von Moltke
  14. Noam A Cohen
  15. Xin Sun  Is a corresponding author
  16. Andrew E Vaughan  Is a corresponding author
  1. University of California, San Diego, United States
  2. University of Pennsylvania, United States
  3. University of California, San Francisco, United States
  4. University of Washington, United States
  5. 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.

The following data sets were generated

Article and author information

Author details

  1. Justinn Barr

    Department of Pediatrics, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Maria Elena Gentile

    Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sunyoung Lee

    Department of Pediatrics, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Maya E Kotas

    Division of Pulmonary, Critical Care, Allergy & Sleep Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Maria Fernanda de Mello Costa

    Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nicolas P Holcomb

    Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Abigail Jaquish

    Department of Pediatrics, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Gargi Palashikar

    Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Marcella Soewignjo

    Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Margaret McDaniel

    Department of Immunology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Ichiro Matsumoto

    Monell Chemical Senses Center, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Robert Margolskee

    Monell Chemical Senses Center, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Jakob Von Moltke

    Department of Immunology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Noam A Cohen

    Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Xin Sun

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    For correspondence
    xinsun@health.ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8387-4966
  16. Andrew E Vaughan

    Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States
    For correspondence
    andrewva@vet.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5740-643X

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.

Reviewing Editor

  1. Paul W Noble, Cedars-Sinai Medical Centre, United States

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).

Version history

  1. Received: February 22, 2022
  2. Preprint posted: March 11, 2022 (view preprint)
  3. Accepted: September 7, 2022
  4. Accepted Manuscript published: September 8, 2022 (version 1)
  5. Version of Record published: October 11, 2022 (version 2)

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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  1. Justinn Barr
  2. Maria Elena Gentile
  3. Sunyoung Lee
  4. Maya E Kotas
  5. Maria Fernanda de Mello Costa
  6. Nicolas P Holcomb
  7. Abigail Jaquish
  8. Gargi Palashikar
  9. Marcella Soewignjo
  10. Margaret McDaniel
  11. Ichiro Matsumoto
  12. Robert Margolskee
  13. Jakob Von Moltke
  14. Noam A Cohen
  15. Xin Sun
  16. Andrew E Vaughan
(2022)
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

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https://doi.org/10.7554/eLife.78074

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