Chronic itch is a debilitating disorder that can last for months or years. Eczema, or atopic dermatitis, is the most common cause for chronic itch, affecting one in ten people worldwide. Many treatments for the condition are ineffective, and the exact cause of the disease is unknown, but many different types of cells are likely involved. These include skin cells and inflammation-promoting immune cells, as well as nerve cells that detect inflammation, relay itch and pain information to the brain, and regulate the immune system.

Learning more about how these cells interact in eczema may help scientists find better treatments for the condition. So far, a lot of research has focused on static ‘snapshots’ of mature eczema lesions from human skin or animal models. These studies have identified abnormalities in genes or cells, but have not revealed how these genes and cells interact over time to cause chronic itch and inflammation.

Now, Walsh et al. reveal that immune cells called neutrophils trigger chronic itch in eczema. The experiments involved mice with a condition that mimics eczema, and showed that removing the neutrophils in these mice alleviated their itching. They also showed that dramatic and rapid changes occur in the nervous system of mice suffering from the eczema-like condition. For example, excess nerves grow in the animals’ damaged skin, genes in the nerves that detect sensations become hyperactive, and changes occur in the spinal cord that have been linked to nerve pain. When neutrophils are absent, these changes do not take place.

These findings show that neutrophils play a key role in chronic itch and inflammation in eczema. Drugs that target neutrophils, which are already used to treat other diseases, might help with chronic itch, but they would need to be tested before they can be used on people with eczema.

Chronic itch is a debilitating disorder that affects millions of people worldwide (Matterne et al., 2011; Mollanazar et al., 2016; Dalgard et al., 2015). It is a symptom of a number of skin diseases and systemic disorders, as well as a side effect of a growing list of medications. Like chronic pain, chronic itch can be a disease in and of itself (Ständer and Steinhoff, 2002; Oaklander, 2011; Dhand and Aminoff, 2014). Unlike acute itch, which can facilitate removal of crawling insects, parasites, or irritants, persistent scratching in chronic itch disorders has no discernable benefit; scratching damages skin, leading to secondary infection, disfiguring lesions, and exacerbation of disease severity (Mollanazar et al., 2016; Yosipovitch and Papoiu, 2008; Ikoma et al., 2006). The most common chronic itch disorder is atopic dermatitis (AD; commonly known as eczema), which affects fifteen million people in the United States alone (Spergel and Paller, 2003). Severe AD can trigger the atopic march, where chronic itch and inflammation progress to food allergy, allergic rhinitis, and asthma (Spergel and Paller, 2003; Zheng et al., 2011).

Little is known about the underlying mechanisms that drive chronic itch pathogenesis. As such, studies of human chronic itch disorders have sought to identify candidate mechanisms of disease progression. A number of studies have identified biomarkers and disease genes in itchy human AD lesions (Ewald et al., 2017; Choy et al., 2012; Guttman-Yassky et al., 2009; Suárez-Fariñas et al., 2013; Jabbari et al., 2012). Indeed, a recent study compared the transcriptomes of healthy skin to itchy and non-itchy skin from psoriasis and AD patients, revealing dramatic changes in expression of genes associated with cytokines, immune cells, epithelial cells, and sensory neurons (Nattkemper et al., 2018). However, due to the difficulty in staging lesion development and obtaining staged samples from patients, there is currently no temporal map of when individual molecules and cell types contribute to chronic itch pathogenesis. Furthermore, the use of human patient data does not allow for rigorous mechanistic study of how disease genes contribute to chronic itch. To this end, we used a well-characterized inducible animal model of itch to define where, when, and how these genes identified from patient data contribute to chronic itch pathogenesis.

We employed the MC903 mouse model of AD and the atopic march (Dai et al., 2017; Li et al., 2009; Li et al., 2006; Zhang et al., 2009; Moosbrugger-Martinz et al., 2017) to provide a framework within which to identify the molecules and cells that initiate the development of atopic itch. The MC903 model is ideal for our approach because of its highly reproducible phenotypes that closely resemble human AD and its ability to induce the development of lesions and scratching (Li et al., 2009; Li et al., 2006; Zhang et al., 2009; Oetjen et al., 2017; Morita et al., 2015; Kim et al., 2019). By contrast, it is difficult to synchronously time the development of lesions in commonly used genetic models of AD, such as filaggrin mutant mice or Nc/Nga mice. Another advantage of the MC903 model is that it displays collectively more hallmarks of human AD than any one particular genetic mouse model. For example, the commonly used IL-31^tg overexpressor model (Cevikbas et al., 2014; Meng et al., 2018) lacks strong Th2 induction, (Martel et al., 2017) and itch behaviors have not yet been rigorously characterized in the keratinocyte-TSLP overexpressor model. As MC903 is widely used to study the chronic phase of AD, we hypothesized that MC903 could also be used to define the early mechanisms underlying the development of chronic itch, beginning with healthy skin. We performed RNA-seq of skin at key time points in the model. We complemented this approach with measurements of itch behavior and immune cell infiltration. The primary goal of our study was to identify the inciting molecules and cell types driving development of chronic itch. To that end, we show that infiltration of neutrophils into skin is required for development of chronic itch. Additionally, we demonstrate that neutrophils direct early hyperinnervation of skin, and the upregulation of itch signaling molecules and activity-induced genes in sensory neurons. Finally, we identify CXCL10/CXCR3 signaling as a key link between infiltrating neutrophils and sensory neurons that drives itch behaviors.

There is great interest in unraveling the neuroimmune interactions that promote acute and chronic itch. Here, we show that neutrophils are essential for the early development of MC903-evoked itch. We further show that the recruitment of neutrophils to the skin is sufficient to drive itch behaviors within minutes of infiltration. While neutrophils are known to release a variety of pruritogens, their roles in itch and AD were not studied (Hashimoto et al., 2018). Only a few studies have even reported the presence of neutrophils in human AD lesions (Choy et al., 2012; Koro et al., 1999; Mihm et al., 1976; Shalit et al., 1987). Neutrophils have been implicated in psoriatic inflammation and inflammatory pain, (Sumida et al., 2014; Perkins and Tracey, 2000; Guerrero et al., 2008; Cunha et al., 2003; Finley et al., 2013; Carreira et al., 2013; Levine et al., 2006; Schön et al., 2000) where they are thought to rapidly respond to tissue injury and inflammation, (Oyoshi et al., 2012) but they have not been directly linked to itch.

There is a strong precedence for immune cell-neuronal interactions that drive modality-specific outcomes, such as itch versus pain, under distinct inflammatory conditions. In allergy, mast cells infiltrate the upper dermis and epidermis and release pruritogens to cause itch, (Solinski et al., 2019b; Meixiong et al., 2019) whereas in tissue injury, mast cell activation can trigger pain hypersensitivity (Chatterjea and Martinov, 2015). Likewise, neutrophils are also implicated in both pain and itch. For example, pyoderma gangrenosum, which causes painful skin ulcerations recruits neutrophils to the deep dermal layers to promote tissue damage and pain (Hashimoto et al., 2018). In AD, neutrophils are recruited to the upper dermis and epidermis, (Choy et al., 2012; Shalit et al., 1987) and we now show that neutrophils trigger itch in AD. Adding to the complex and diverse roles of neutrophils, neutrophils recruited to subcutaneous sites during invasive streptococcal infection alleviate pain by clearing the tissue of bacteria (Pinho-Ribeiro et al., 2018). Several potential mechanisms may explain these diverse effects of neutrophils. First, the location of the inflammatory insult could promote preferential engagement of pain versus itch nerve fibers (Hashimoto et al., 2018). This is supported by observations that neutrophil-derived reactive oxygen species and leukotrienes can promote either itch or pain under different inflammatory conditions (Salvemini et al., 2011; Bautista et al., 2006; Liu and Ji, 2012; Caceres et al., 2009). Second, it has been proposed that there are distinct functional subsets of neutrophils that release modality-specific inflammatory mediators (Wang, 2018). Third, the disease-specific inflammatory milieu may induce neutrophils to specifically secrete mediators of either itch or pain. Indeed, all three of these mechanisms have been proposed to underlie the diverse functions of microglia and macrophages in homeostasis, tissue repair, injury, and neurodegenerative disease (Hammond et al., 2018). It will be of great interest to the field to decipher the distinct mechanisms by which neutrophils and other immune cells interact with the nervous system to drive pain and itch.

In addition to neutrophils, TSLP signaling and the Type two immune response plays an important role in the development of itch in the second week of the MC903 model. Dendritic cells, mast cells, basophils, and CD4⁺ T cells are all major effectors of the TSLP inflammatory pathway in the skin. We propose that neutrophils play an early role in triggering itch and also contribute to chronic itch in parallel with the TSLP-Type two response. While we have ruled out an early role for TSLP signaling and basophils and CD4⁺ T cells in early itch, other cell types such as mast cells, which have recently been linked directly to chronic itch, (Solinski et al., 2019b; Meixiong et al., 2019) and dendritic cells may be playing an important role in setting the stage for itch and inflammation prior to infiltration of neutrophils.

Given the large magnitude of the itch deficit in the neutrophil-depleted mice, we were surprised to find fewer expression differences in MC903-dependent, AD-associated genes between neutrophil depleted and non-depleted mice than were observed between WT and TSLPR KO mice. One of the few exceptions were the Th1-associated genes Cxcl9/10/11 (Ewald et al., 2017; Brunner et al., 2017). We found that induction of these genes and of CXCL10 protein was completely dependent on neutrophils. While our results do not identify the particular cell type(s) responsible for neutrophil-dependent CXCL10 production, a number of cell types present in skin have been shown to produce CXCL10, including epithelial keratinocytes, myeloid cells, and sensory neurons (Hashimoto et al., 2018; Ioannidis et al., 2016; Kanda et al., 2007; Koga et al., 2008; Michalec et al., 2002; Padovan et al., 2002; Tamassia et al., 2007). In support of a role for neutrophils in promoting chronic itch, we observed striking differences in neutrophil-dependent gene expression in the spinal cord, where expression of activity-induced genes and the chronic itch gene Lcn2 were markedly attenuated by loss of neutrophils. Moreover, we also demonstrate that depletion of neutrophils in the second week of the MC903 model can attenuate chronic itch-evoked scratching. In examining previous characterizations of both human and mouse models of AD and related chronic itch disorders, several studies report that neutrophils and/or neutrophil chemokines are indeed present in chronic lesions (Ewald et al., 2017; Choy et al., 2012; Guttman-Yassky et al., 2009; Suárez-Fariñas et al., 2013; Jabbari et al., 2012; Nattkemper et al., 2018; Li et al., 2017; Saunders et al., 2016; Andersson, 2015; Liu et al., 2019; Malik et al., 2017). Our observations newly implicate neutrophils in setting the stage for the acute-to-chronic itch transition by triggering molecular changes necessary to develop a chronic, itchy lesion and also contributing to persistent itch.

Additionally, we demonstrate a novel role of CXCR3 signaling in MC903-induced itch. The CXCR3 ligand CXCL10 contributes to mouse models of acute and allergic itch (Qu et al., 2015; Qu et al., 2017; Jing et al., 2018); however, its role in chronic itch was previously unknown. We speculate that the residual itch behaviors after administration of the CXCR3 antagonist could be due to TSLPR-dependent IL-4 signaling, as TSLPR-deficient mice display reduced itch behaviors by the second week of the model, or due to some other aspect of neutrophil signaling, such as release of proteases, leukotrienes, prostaglandins, or reactive oxygen species, all of which can directly trigger itch via activation of somatosensory neurons (Hashimoto et al., 2018). Our observations are in alignment with a recent study showing that dupilumab, a new AD drug that blocks IL4Rα, a major downstream effector of the TSLP signaling pathway, does not significantly reduce CXCL10 protein levels in human AD lesions (Hamilton et al., 2014). Taken together, these findings suggest that the TSLP/IL-4 and neutrophil/CXCL10 pathways are not highly interdependent, and supports our findings that Il4 transcript is robustly upregulated in the absence of neutrophils. Additionally, targeting IL4Rα signaling has been successful in treating itch and inflammation in some, but not all, AD patients (Simpson et al., 2016). We propose that biologics or compounds targeting neutrophils and/or the CXCR3 pathway may be useful for AD that is incompletely cleared by dupilumab monotherapy. Drugs targeting neutrophils are currently in clinical trials for the treatment of psoriasis, asthma, and other inflammatory disorders. For example, MDX-1100, a biologic that targets CXCL10, has already shown efficacy for treatment of rheumatoid arthritis in phase II clinical trials (Yellin et al., 2012). While rheumatoid arthritis and AD have distinct etiologies, (Scott et al., 2010) our body of work indicates that CXCL10 or CXCR3 may be promising targets for treating chronic itch. Our findings may also be applicable to other itch disorders where neutrophil chemoattractants and/or CXCL10 are also elevated, such as psoriasis and allergic contact dermatitis. Overall, our data suggest that neutrophils incite itch and inflammation in early AD through several mechanisms, including: 1) directly triggering itch upon infiltration into the skin, as shown by acute injection of CXCL1, and, 2) indirectly triggering itch by altering expression of endogenous pruritogens (e.g. induction of Cxcl10 expression; Hashimoto et al., 2018; Ioannidis et al., 2016; Kanda et al., 2007; Koga et al., 2008; Michalec et al., 2002; Padovan et al., 2002; Tamassia et al., 2007). Together, these direct and indirect mechanisms for neutrophil-dependent itch may explain why neutrophils have a dramatic effect on scratching behaviors on not only days eight and twelve but also day five of the model, when neutrophils are recruited in large numbers, but CXCR3 ligands are not as robustly induced.

More generally, our study provides a framework for understanding how and when human chronic itch disease genes contribute to the distinct stages of AD pathogenesis. Our analysis of MC903-evoked transcriptional changes suggests we may be able to extend findings in the model not only to atopic dermatitis, but also to related disorders, including specific genetic forms of atopy. For example, we provide evidence that MC903 treatment may also model the filaggrin loss-of-function mutations, which are a key inciting factor in human heritable atopic disease (Palmer et al., 2006; Sandilands et al., 2007). There are many rich datasets looking at mature patient lesions and datasets for mature lesions in other mouse models of chronic itch (Ewald et al., 2017; Choy et al., 2012; Guttman-Yassky et al., 2009; Jabbari et al., 2012; Nattkemper et al., 2018; Oetjen et al., 2017; Liu et al., 2019; Liu et al., 2016). Our study adds a temporal frame of reference to these existing datasets and sets the stage for probing the function of AD disease genes in greater detail. Furthermore, we have mapped the time course of gene expression changes in primary sensory ganglia and spinal cord during chronic itch development. We show that the MC903 model recapitulates several hallmarks of neuropathic disease on a time course much shorter than has been reported for chronic itch, or chronic pain. Nervous system tissues are extremely difficult to obtain from human AD patients, and thus little is known regarding the neuronal changes in chronic itch disorders in both mouse models and human patients. Our findings can now be compared to existing and future datasets examining neuronal changes in chronic pain, diabetic neuropathy, shingles, neuropathic itch, psoriasis, and other inflammatory disorders where neuronal changes are poorly understood but may contribute to disease progression. The early changes we see in skin innervation, sensory ganglia, and spinal cord dovetail with recent studies examining neuroimmune interactions in other inflammatory conditions, (Pinho-Ribeiro et al., 2018; Baral et al., 2018; Pinho-Ribeiro et al., 2017; Blake et al., 2018) which all implicate early involvement of sensory neurons in the pathogenesis of inflammatory diseases.

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 Source data 1. Code used to analyze data is available at https://github.com/rzhill/10.1101-653873 (copy archived at https://github.com/elifesciences-publications/10.1101-653873).

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Author details

1. Carolyn M Walsh

   Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing, Performed flow cytometry and behavior experiments, and made substantial contributions to Figures 1C, 1G, 2A, 2D, 2E, 2F, 2I, Figure 2—figure supplement 2, and Figure 2—figure supplement 4

   Contributed equally with

   Rose Z Hill

   Competing interests

   No competing interests declared

   Additional information

   Author order was randomly determined by a coin flip

2. Rose Z Hill

   Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

   Present address

   The Scripps Research Institute, La Jolla, United States

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing, Performed flow cytometry, behavior, skin, somatosensory ganglia and spinal cord RNA-seq, IHC, ELISA, and made substantial contributions to Figures 1A, 1B, 1C, 1H, 1I, 1J, Figure 1—figure supplement 1, Figure 1—figure supplement 7, Figure 1—figure supplement 9, Figures 2J, 2K, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 4A, 4B, 4C, 4D, 4E, 4F, 4G, Figure 4—figure supplement 1, and Figure 4—figure supplement 2

   Contributed equally with

   Carolyn M Walsh

   Competing interests

   No competing interests declared

   Additional information

   Author order was randomly determined by a coin flip

   "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

   Contribution

   Conceptualization, Investigation, Methodology, Writing—review and editing, Performed flow cytometry, keratinocyte RNA-Seq and behavior experiments, and made substantial contributions to Figure 1—figure supplement 6, Figure 1—figure supplement 10, Figures 2A, 2E, Figure 2—figure supplement 2, and Figure 2—figure supplement 3

   Competing interests

   No competing interests declared

4. Jacques Deguine

   Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Writing—review and editing, Performed flow cytometry experiments, and made substantial contributions to Figures 2A, 2B, 2C, 2E, 2G, 2H, Figure 2—figure supplement 1, Figure 2—figure supplement 2, and Figure 2—figure supplement 4

   Competing interests

   No competing interests declared

5. Emily C Brock

   Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Writing—review and editing, Performed flow cytometry and behavior experiments, and made substantial contributions to Figures 1C, 1E, 1F, Figure 1—figure supplement 5, Figures 2A, 2B, 2C, 2F, 2G, 2H, Figure 2—figure supplement 1, Figures 2—figure supplement 2, and Figure 2—figure supplement 4

   Competing interests

   No competing interests declared

6. Natalie Kucirek

   Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

   Contribution

   Investigation, Writing—review and editing, Performed behavior experiments, and made substantial contributions to Figures 1C and 2F

   Competing interests

   No competing interests declared

7. Ziad Rifi

   Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

   Contribution

   Investigation, Writing—review and editing, Performed IHC experiments, and made substantial contributions to Figures 3C, 3D, 3E, and 3F

   Competing interests

   No competing interests declared

8. Jessica Wei

   Vision Science Program, School of Optometry, University of California, Berkeley, Berkeley, United States

   Contribution

   Investigation, Performed mass spectrometry experiments, and made substantial contributions to Figure 1—figure supplement 10

   Competing interests

   No competing interests declared

   "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

   Contribution

   Resources, Supervision, Funding acquisition, Methodology, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

10. Rachel B Brem

    1. Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, United States
    2. Buck Institute for Research on Aging, Novato, United States

    Contribution

    Conceptualization, Resources, Supervision, Funding acquisition, Methodology, Project administration, Writing—review and editing

    Competing interests

    No competing interests declared

11. Diana M Bautista

    1. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    2. Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States

    Contribution

    Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Methodology, Writing—original draft, Project administration, Writing—review and editing

    For correspondence

    dbautista@berkeley.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-6809-8951

12. Gregory M Barton

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

    Contribution

    Conceptualization, Resources, Supervision, Funding acquisition, Methodology, Project administration, Writing—review and editing

    For correspondence

    barton@berkeley.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-3793-0100

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