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.

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).

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.

Metrics

  • 7,284
    views
  • 1,044
    downloads
  • 103
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Gregory T Walker, Araceli Perez-Lopez ... Manuela Raffatellu
    Research Article Updated

    The chemokine CCL28 is highly expressed in mucosal tissues, but its role during infection is not well understood. Here, we show that CCL28 promotes neutrophil accumulation in the gut of mice infected with Salmonella and in the lung of mice infected with Acinetobacter. Neutrophils isolated from the infected mucosa expressed the CCL28 receptors CCR3 and, to a lesser extent, CCR10, on their surface. The functional consequences of CCL28 deficiency varied between the two infections: Ccl28−/− mice were highly susceptible to Salmonella gut infection but highly resistant to otherwise lethal Acinetobacter lung infection. In vitro, unstimulated neutrophils harbored pre-formed intracellular CCR3 that was rapidly mobilized to the cell surface following phagocytosis or inflammatory stimuli. Moreover, CCL28 stimulation enhanced neutrophil antimicrobial activity, production of reactive oxygen species, and formation of extracellular traps, all processes largely dependent on CCR3. Consistent with the different outcomes in the two infection models, neutrophil stimulation with CCL28 boosted the killing of Salmonella but not Acinetobacter. CCL28 thus plays a critical role in the immune response to mucosal pathogens by increasing neutrophil accumulation and activation, which can enhance pathogen clearance but also exacerbate disease depending on the mucosal site and the infectious agent.

    1. Evolutionary Biology
    2. Immunology and Inflammation
    Shang Geng, Xing Lv ... Tianjun Xu
    Research Article

    The incessant arms race between viruses and hosts has led to numerous evolutionary innovations that shape life’s evolution. During this process, the interactions between viral receptors and viruses have garnered significant interest since viral receptors are cell surface proteins exploited by viruses to initiate infection. Our study sheds light on the arms race between the MDA5 receptor and 5’ppp-RNA virus in a lower vertebrate fish, Miichthys miiuy. Firstly, the frequent and independent loss events of RIG-I in vertebrates prompted us to search for alternative immune substitutes, with homology-dependent genetic compensation response (HDGCR) being the main pathway. Our further analysis suggested that MDA5 of M. miiuy and Gallus gallus, the homolog of RIG-I, can replace RIG-I in recognizing 5’ppp-RNA virus, which may lead to redundancy of RIG-I and loss from the species genome during evolution. Secondly, as an adversarial strategy, 5’ppp-RNA SCRV can utilize the m6A methylation mechanism to degrade MDA5 and weaken its antiviral immune ability, thus promoting its own replication and immune evasion. In summary, our study provides a snapshot into the interaction and coevolution between vertebrate and virus, offering valuable perspectives on the ecological and evolutionary factors that contribute to the diversity of the immune system.