Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis
- University of California, Berkeley, United States
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.
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RNA-seq of tissues from MC903- and Ethanol-treated miceNCBI Gene Expression Omnibus, GSE132173.
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SLIGRL-induced gene expression changes in NHEK cellsNCBI Gene Expression Omnibus, GSE132174.
Article and author information
Author details
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
- Andrew J King, University of Oxford, United Kingdom
Version history
- Received: May 14, 2019
- Accepted: October 17, 2019
- Accepted Manuscript published: October 21, 2019 (version 1)
- Version of Record published: November 29, 2019 (version 2)
- 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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Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis
eLife 8:e48448.
https://doi.org/10.7554/eLife.48448
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