1. Immunology and Inflammation
  2. Neuroscience
Download icon

Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis

  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  Is a corresponding author
  12. Diana M Bautista  Is a corresponding author
  1. University of California, Berkeley, United States
Research Article
  • Cited 16
  • Views 3,247
  • Annotations
Cite this article as: eLife 2019;8:e48448 doi: 10.7554/eLife.48448

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).

Reviewing Editor

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

Publication 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.

Metrics

  • 3,247
    Page views
  • 555
    Downloads
  • 16
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

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

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

Categories and tags

Research organism

    1. Related to

    Autoimmunity: Bringing on the itch

    Daniel A Waizman et al.
  2. Further reading

Further reading

    1. Immunology and Inflammation
    2. Neuroscience

    Autoimmunity: Bringing on the itch

    Daniel A Waizman et al.
    Insight

    Neutrophils are the first immune cells that enter the skin and cause itch in atopic dermatitis.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    IL-33 promotes innate lymphoid cell-dependent IFN-γ production required for innate immunity to Toxoplasma gondii

    Joseph T Clark et al.
    Research Article Updated

    IL-33 is an alarmin required for resistance to the parasite Toxoplasma gondii, but its role in innate resistance to this organism is unclear. Infection with T. gondii promotes increased stromal cell expression of IL-33, and levels of parasite replication correlate with release of IL-33 in affected tissues. In response to infection, a subset of innate lymphoid cells (ILC) emerges composed of IL-33R+ NK cells and ILC1s. In Rag1−/−mice, where NK cells and ILC1 production of IFN-γ mediate innate resistance to T. gondii, the loss of the IL-33R resulted in reduced ILC responses and increased parasite replication. Furthermore, administration of IL-33 to Rag1−/− mice resulted in a marked decrease in parasite burden, increased production of IFN-γ, and the recruitment and expansion of inflammatory monocytes associated with parasite control. These protective effects of exogenous IL-33 were dependent on endogenous IL-12p40 and the ability of IL-33 to enhance ILC production of IFN-γ. These results highlight that IL-33 synergizes with IL-12 to promote ILC-mediated resistance to T. gondii.

    1. Cell Biology
    2. Immunology and Inflammation

    Molecular tracking devices quantify antigen distribution and archiving in the murine lymph node

    Shannon M Walsh et al.
    Tools and Resources Updated

    The detection of foreign antigens in vivo has relied on fluorescent conjugation or indirect read-outs such as antigen presentation. In our studies, we found that these widely used techniques had several technical limitations that have precluded a complete picture of antigen trafficking or retention across lymph node cell types. To address these limitations, we developed a ‘molecular tracking device’ to follow the distribution, acquisition, and retention of antigen in the lymph node. Utilizing an antigen conjugated to a nuclease-resistant DNA tag, acting as a combined antigen-adjuvant conjugate, and single-cell mRNA sequencing, we quantified antigen abundance in the lymph node. Variable antigen levels enabled the identification of caveolar endocytosis as a mechanism of antigen acquisition or retention in lymphatic endothelial cells. Thus, these molecular tracking devices enable new approaches to study dynamic tissue dissemination of antigen-adjuvant conjugates and identify new mechanisms of antigen acquisition and retention at cellular resolution in vivo.