Abstract

Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the development of itch and the acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. Neutrophils were also required for several key hallmarks of chronic itch, including skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 antagonism attenuates chronic itch.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Data from RNA-seq experiments are uploaded to GEO under accession codes GSE132173 and GSE132174. Processed sequencing data (DESeq output tables) are provided as a Supplementary Data file. Code used to analyze data is available at https://github.com/rzhill/10.1101-653873.

The following data sets were generated

Article and author information

Author details

  1. Carolyn M Walsh

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Rose Z Hill

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9558-6400
  3. Jamie Schwendinger-Schreck

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jacques Deguine

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Emily C Brock

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Natalie Kucirek

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ziad Rifi

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jessica Wei

    Vision Science Program, School of Optometry, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7329-2812
  9. Karsten Gronert

    Vision Science Program, School of Optometry, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Rachel B Brem

    Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Gregory M Barton

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    barton@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3793-0100
  12. Diana M Bautista

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    dbautista@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6809-8951

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR059385)

  • Diana M Bautista

National Eye Institute (EY026082)

  • Karsten Gronert

National Institute of Neurological Disorders and Stroke (NS098097)

  • Rachel B Brem
  • Diana M Bautista

National Institute of Neurological Disorders and Stroke (NS07224)

  • Rachel B Brem
  • Diana M Bautista

Howard Hughes Medical Institute

  • Diana M Bautista

National Institute of Allergy and Infectious Diseases (AI072429)

  • Gregory M Barton

National Institute of Allergy and Infectious Diseases (AI063302)

  • Gregory M Barton

National Institute of Allergy and Infectious Diseases (AI104914)

  • Gregory M Barton

National Institute of Allergy and Infectious Diseases (AI105184)

  • Gregory M Barton

Burroughs Wellcome Fund

  • Gregory M Barton

Human Frontier Science Program (LT-000081/2013-L)

  • Jacques Deguine

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andrew J King, University of Oxford, United Kingdom

Ethics

Animal experimentation: All mice were housed in standard conditions in accordance with standards approved by the Animal Care and Use Committee of the University of California Berkeley. All experiments were performed under the policies and recommendations of the International Association for the Study of Pain and approved by the University of California Berkeley Animal Care and Use Committee (Protocol Number: 2017-02-9550).

Version history

  1. Received: May 14, 2019
  2. Accepted: October 17, 2019
  3. Accepted Manuscript published: October 21, 2019 (version 1)
  4. Version of Record published: November 29, 2019 (version 2)
  5. Version of Record updated: January 6, 2020 (version 3)

Copyright

© 2019, Walsh 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. Carolyn M Walsh
  2. Rose Z Hill
  3. Jamie Schwendinger-Schreck
  4. Jacques Deguine
  5. Emily C Brock
  6. Natalie Kucirek
  7. Ziad Rifi
  8. Jessica Wei
  9. Karsten Gronert
  10. Rachel B Brem
  11. Gregory M Barton
  12. Diana M Bautista
(2019)
Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis
eLife 8:e48448.
https://doi.org/10.7554/eLife.48448

Share this article

https://doi.org/10.7554/eLife.48448

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