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).

1. 1. Bautista DM
   2. Hill RZ

   (2019) NCBI Gene Expression Omnibus

   ID GSE132173. RNA-seq of tissues from MC903- and Ethanol-treated mice.

   https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE132173
2. 1. Bautista DM

   (2019) NCBI Gene Expression Omnibus

   ID GSE132174. SLIGRL-induced gene expression changes in NHEK cells.

   https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE132174

1. 1. Anders S
   2. McCarthy DJ
   3. Chen Y
   4. Okoniewski M
   5. Smyth GK
   6. Huber W
   7. Robinson MD

   (2013) Count-based differential expression analysis of RNA sequencing data using R and bioconductor

   Nature Protocols 8:1765–1786.

   https://doi.org/10.1038/nprot.2013.099

   • PubMed
   • Google Scholar
2. 1. Anders S
   2. Huber W

   (2012) Differential expression of RNA-Seq data at the gene level–the DESeq package

   Differential expression of RNA-Seq data at the gene level–the DESeq package, Heidelberg, http://watson.nci.nih.gov/bioc_mirror/packages/2.11/bioc/vignettes/DESeq/inst/doc/DESeq.pdf.

   http://watson.nci.nih.gov/bioc_mirror/packages/2.11/bioc/vignettes/DESeq/inst/doc/DESeq.pdf

   • Google Scholar
3. Thesis

   1. Andersson S

   (2015) The role of mast cells and mast cell mediators in the development of atopic dermatitis in a mouse model

   SLU, Department of Biomedical Sciences and Veterinary Public Health, Uppsala, Sweden.

   https://stud.epsilon.slu.se/6630/

   • Google Scholar
4. 1. Baral P
   2. Umans BD
   3. Li L
   4. Wallrapp A
   5. Bist M
   6. Kirschbaum T
   7. Wei Y
   8. Zhou Y
   9. Kuchroo VK
   10. Burkett PR
   11. Yipp BG
   12. Liberles SD
   13. Chiu IM

   (2018) Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia

   Nature Medicine 24:417–426.

   https://doi.org/10.1038/nm.4501

   • PubMed
   • Google Scholar
5. 1. Bautista DM
   2. Jordt SE
   3. Nikai T
   4. Tsuruda PR
   5. Read AJ
   6. Poblete J
   7. Yamoah EN
   8. Basbaum AI
   9. Julius D

   (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents

   Cell 124:1269–1282.

   https://doi.org/10.1016/j.cell.2006.02.023

   • PubMed
   • Google Scholar
6. 1. Blake KJ
   2. Baral P
   3. Voisin T
   4. Lubkin A
   5. Pinho-Ribeiro FA
   6. Adams KL
   7. Roberson DP
   8. Ma YC
   9. Otto M
   10. Woolf CJ
   11. Torres VJ
   12. Chiu IM

   (2018) Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314

   Nature Communications 9:37.

   https://doi.org/10.1038/s41467-017-02448-6

   • PubMed
   • Google Scholar
7. 1. Briot A
   2. Deraison C
   3. Lacroix M
   4. Bonnart C
   5. Robin A
   6. Besson C
   7. Dubus P
   8. Hovnanian A

   (2009) Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in netherton syndrome

   The Journal of Experimental Medicine 206:1135–1147.

   https://doi.org/10.1084/jem.20082242

   • PubMed
   • Google Scholar
8. 1. Briot A
   2. Lacroix M
   3. Robin A
   4. Steinhoff M
   5. Deraison C
   6. Hovnanian A

   (2010) Par2 inactivation inhibits early production of TSLP, but not cutaneous inflammation, in netherton syndrome adult mouse model

   Journal of Investigative Dermatology 130:2736–2742.

   https://doi.org/10.1038/jid.2010.233

   • PubMed
   • Google Scholar
9. 1. Brunner PM
   2. Guttman-Yassky E
   3. Leung DY

   (2017) The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies

   Journal of Allergy and Clinical Immunology 139:S65–S76.

   https://doi.org/10.1016/j.jaci.2017.01.011

   • PubMed
   • Google Scholar
10. 1. Caceres AI
    2. Brackmann M
    3. Elia MD
    4. Bessac BF
    5. del Camino D
    6. D'Amours M
    7. Witek JS
    8. Fanger CM
    9. Chong JA
    10. Hayward NJ
    11. Homer RJ
    12. Cohn L
    13. Huang X
    14. Moran MM
    15. Jordt SE

    (2009) A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma

    PNAS 106:9099–9104.

    https://doi.org/10.1073/pnas.0900591106

    • PubMed
    • Google Scholar
11. 1. Carpino N
    2. Thierfelder WE
    3. Chang MS
    4. Saris C
    5. Turner SJ
    6. Ziegler SF
    7. Ihle JN

    (2004) Absence of an essential role for thymic stromal lymphopoietin receptor in murine B-cell development

    Molecular and Cellular Biology 24:2584–2592.

    https://doi.org/10.1128/MCB.24.6.2584-2592.2004

    • PubMed
    • Google Scholar
12. 1. Carreira EU
    2. Carregaro V
    3. Teixeira MM
    4. Moriconi A
    5. Aramini A
    6. Verri WA
    7. Ferreira SH
    8. Cunha FQ
    9. Cunha TM

    (2013) Neutrophils recruited by CXCR1/2 signalling mediate post-incisional pain

    European Journal of Pain 17:654–663.

    https://doi.org/10.1002/j.1532-2149.2012.00240.x

    • PubMed
    • Google Scholar
13. 1. Cevikbas F
    2. Wang X
    3. Akiyama T
    4. Kempkes C
    5. Savinko T
    6. Antal A
    7. Kukova G
    8. Buhl T
    9. Ikoma A
    10. Buddenkotte J
    11. Soumelis V
    12. Feld M
    13. Alenius H
    14. Dillon SR
    15. Carstens E
    16. Homey B
    17. Basbaum A
    18. Steinhoff M

    (2014) A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1

    Journal of Allergy and Clinical Immunology 133:448–460.

    https://doi.org/10.1016/j.jaci.2013.10.048

    • PubMed
    • Google Scholar
14. 1. Chatterjea D
    2. Martinov T

    (2015) Mast cells: versatile gatekeepers of pain

    Molecular Immunology 63:38–44.

    https://doi.org/10.1016/j.molimm.2014.03.001

    • PubMed
    • Google Scholar
15. 1. Choy DF
    2. Hsu DK
    3. Seshasayee D
    4. Fung MA
    5. Modrusan Z
    6. Martin F
    7. Liu FT
    8. Arron JR

    (2012) Comparative transcriptomic analyses of atopic dermatitis and psoriasis reveal shared neutrophilic inflammation

    Journal of Allergy and Clinical Immunology 130:1335–1343.

    https://doi.org/10.1016/j.jaci.2012.06.044

    • PubMed
    • Google Scholar
16. 1. Cunha JM
    2. Sachs D
    3. Canetti CA
    4. Poole S
    5. Ferreira SH
    6. Cunha FQ

    (2003) The critical role of leukotriene B4 in antigen-induced mechanical hyperalgesia in immunised rats

    British Journal of Pharmacology 139:1135–1145.

    https://doi.org/10.1038/sj.bjp.0705346

    • PubMed
    • Google Scholar
17. 1. Dai J
    2. Choo MK
    3. Park JM
    4. Fisher DE

    (2017) Topical ROR inverse agonists suppress inflammation in mouse models of atopic dermatitis and acute irritant dermatitis

    Journal of Investigative Dermatology 137:2523–2531.

    https://doi.org/10.1016/j.jid.2017.07.819

    • PubMed
    • Google Scholar
18. 1. Dalgard FJ
    2. Gieler U
    3. Tomas-Aragones L
    4. Lien L
    5. Poot F
    6. Jemec GBE
    7. Misery L
    8. Szabo C
    9. Linder D
    10. Sampogna F
    11. Evers AWM
    12. Halvorsen JA
    13. Balieva F
    14. Szepietowski J
    15. Romanov D
    16. Marron SE
    17. Altunay IK
    18. Finlay AY
    19. Salek SS
    20. Kupfer J

    (2015) The psychological burden of skin diseases: a cross-sectional multicenter study among dermatological out-patients in 13 european countries

    Journal of Investigative Dermatology 135:984–991.

    https://doi.org/10.1038/jid.2014.530

    • PubMed
    • Google Scholar
19. 1. Deftu AF
    2. Filippi A
    3. Shibsaki K
    4. Gheorghe RO
    5. Chiritoiu M
    6. Ristoiu V

    (2017)

    Chemokine (C-X-C motif) ligand 1 (CXCL1) and chemokine (C-X-C motif) ligand 2 (CXCL2) modulate the activity of TRPV1+/IB4+ cultured rat dorsal root ganglia neurons upon short-term and acute application

    Journal of Physiology and Pharmacology 68:385–395.

    • PubMed
    • Google Scholar
20. 1. Deftu AF
    2. Filippi A
    3. Gheorghe RO
    4. Ristoiu V

    (2018) CXCL1 activates TRPV1 via gi/o protein and actin filaments

    Life Sciences 193:282–291.

    https://doi.org/10.1016/j.lfs.2017.09.041

    • PubMed
    • Google Scholar
21. 1. Demehri S
    2. Morimoto M
    3. Holtzman MJ
    4. Kopan R

    (2009) Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma

    PLOS Biology 7:e1000067.

    https://doi.org/10.1371/journal.pbio.1000067

    • PubMed
    • Google Scholar
22. 1. Dhand A
    2. Aminoff MJ

    (2014) The neurology of itch

    Brain 137:313–322.

    https://doi.org/10.1093/brain/awt158

    • PubMed
    • Google Scholar
23. 1. Dong X
    2. Dong X

    (2018) Peripheral and central mechanisms of itch

    Neuron 98:482–494.

    https://doi.org/10.1016/j.neuron.2018.03.023

    • PubMed
    • Google Scholar
24. 1. Ewald DA
    2. Noda S
    3. Oliva M
    4. Litman T
    5. Nakajima S
    6. Li X
    7. Xu H
    8. Workman CT
    9. Scheipers P
    10. Svitacheva N
    11. Labuda T
    12. Krueger JG
    13. Suárez-Fariñas M
    14. Kabashima K
    15. Guttman-Yassky E

    (2017) Major differences between human atopic dermatitis and murine models, as determined by using global transcriptomic profiling

    Journal of Allergy and Clinical Immunology 139:562–571.

    https://doi.org/10.1016/j.jaci.2016.08.029

    • PubMed
    • Google Scholar
25. 1. Finley A
    2. Chen Z
    3. Esposito E
    4. Cuzzocrea S
    5. Sabbadini R
    6. Salvemini D

    (2013) Sphingosine 1-phosphate mediates hyperalgesia via a neutrophil-dependent mechanism

    PLOS ONE 8:e55255.

    https://doi.org/10.1371/journal.pone.0055255

    • PubMed
    • Google Scholar
26. 1. Fogh K
    2. Herlin T
    3. Kragballe K

    (1989) Eicosanoids in skin of patients with atopic dermatitis: prostaglandin E2 and leukotriene B4 are present in biologically active concentrations

    Journal of Allergy and Clinical Immunology 83:450–455.

    https://doi.org/10.1016/0091-6749(89)90132-2

    • PubMed
    • Google Scholar
27. 1. Gao PS
    2. Rafaels NM
    3. Mu D
    4. Hand T
    5. Murray T
    6. Boguniewicz M
    7. Hata T
    8. Schneider L
    9. Hanifin JM
    10. Gallo RL
    11. Gao L
    12. Beaty TH
    13. Beck LA
    14. Leung DY
    15. Barnes KC

    (2010) Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum

    Journal of Allergy and Clinical Immunology 125:1403–1407.

    https://doi.org/10.1016/j.jaci.2010.03.016

    • PubMed
    • Google Scholar
28. 1. Ghasemlou N
    2. Chiu IM
    3. Julien JP
    4. Woolf CJ

    (2015) CD11b+Ly6G- myeloid cells mediate mechanical inflammatory pain hypersensitivity

    PNAS 112:E6808–E6817.

    https://doi.org/10.1073/pnas.1501372112

    • PubMed
    • Google Scholar
29. 1. Gittler JK
    2. Shemer A
    3. Suárez-Fariñas M
    4. Fuentes-Duculan J
    5. Gulewicz KJ
    6. Wang CQ
    7. Mitsui H
    8. Cardinale I
    9. de Guzman Strong C
    10. Krueger JG
    11. Guttman-Yassky E

    (2012) Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis

    Journal of Allergy and Clinical Immunology 130:1344–1354.

    https://doi.org/10.1016/j.jaci.2012.07.012

    • PubMed
    • Google Scholar
30. 1. Guerrero AT
    2. Verri WA
    3. Cunha TM
    4. Silva TA
    5. Schivo IR
    6. Dal-Secco D
    7. Canetti C
    8. Rocha FA
    9. Parada CA
    10. Cunha FQ
    11. Ferreira SH

    (2008) Involvement of LTB4 in zymosan-induced joint nociception in mice: participation of neutrophils and PGE2

    Journal of Leukocyte Biology 83:122–130.

    https://doi.org/10.1189/jlb.0207123

    • PubMed
    • Google Scholar
31. 1. Guttman-Yassky E
    2. Suárez-Fariñas M
    3. Chiricozzi A
    4. Nograles KE
    5. Shemer A
    6. Fuentes-Duculan J
    7. Cardinale I
    8. Lin P
    9. Bergman R
    10. Bowcock AM
    11. Krueger JG

    (2009) Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis

    Journal of Allergy and Clinical Immunology 124:1235–1244.

    https://doi.org/10.1016/j.jaci.2009.09.031

    • PubMed
    • Google Scholar
32. 1. Guttman-Yassky E
    2. Krueger JG

    (2017) Atopic dermatitis and psoriasis: two different immune diseases or one spectrum?

    Current Opinion in Immunology 48:68–73.

    https://doi.org/10.1016/j.coi.2017.08.008

    • PubMed
    • Google Scholar
33. 1. Haas S
    2. Capellino S
    3. Phan NQ
    4. Böhm M
    5. Luger TA
    6. Straub RH
    7. Ständer S

    (2010) Low density of sympathetic nerve fibers relative to substance P-positive nerve fibers in Lesional skin of chronic pruritus and prurigo nodularis

    Journal of Dermatological Science 58:193–197.

    https://doi.org/10.1016/j.jdermsci.2010.03.020

    • PubMed
    • Google Scholar
34. 1. Hamilton JD
    2. Suárez-Fariñas M
    3. Dhingra N
    4. Cardinale I
    5. Li X
    6. Kostic A
    7. Ming JE
    8. Radin AR
    9. Krueger JG
    10. Graham N
    11. Yancopoulos GD
    12. Pirozzi G
    13. Guttman-Yassky E

    (2014) Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis

    Journal of Allergy and Clinical Immunology 134:1293–1300.

    https://doi.org/10.1016/j.jaci.2014.10.013

    • PubMed
    • Google Scholar
35. 1. Hammond TR
    2. Robinton D
    3. Stevens B

    (2018) Microglia and the brain: complementary partners in development and disease

    Annual Review of Cell and Developmental Biology 34:523–544.

    https://doi.org/10.1146/annurev-cellbio-100616-060509

    • PubMed
    • Google Scholar
36. 1. Hashimoto T
    2. Rosen JD
    3. Sanders KM
    4. Yosipovitch G

    (2018) Possible role of neutrophils in itch

    Itch 3:e17.

    https://doi.org/10.1097/itx.0000000000000017

    • Google Scholar
37. 1. Hidaka T
    2. Ogawa E
    3. Kobayashi EH
    4. Suzuki T
    5. Funayama R
    6. Nagashima T
    7. Fujimura T
    8. Aiba S
    9. Nakayama K
    10. Okuyama R
    11. Yamamoto M

    (2017) The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin

    Nature Immunology 18:64–73.

    https://doi.org/10.1038/ni.3614

    • PubMed
    • Google Scholar
38. 1. Hill RZ
    2. Hoffman BU
    3. Morita T
    4. Campos SM
    5. Lumpkin EA
    6. Brem RB
    7. Bautista DM

    (2018) The signaling lipid sphingosine 1-phosphate regulates mechanical pain

    eLife 7:e33285.

    https://doi.org/10.7554/eLife.33285

    • Google Scholar
39. Software

    1. Hill RZ

    (2019) 10.1101-653873, version bcbb047

    Github.

    https://github.com/rzhill/10.1101-653873
40. 1. Huang J
    2. Polgár E
    3. Solinski HJ
    4. Mishra SK
    5. Tseng PY
    6. Iwagaki N
    7. Boyle KA
    8. Dickie AC
    9. Kriegbaum MC
    10. Wildner H
    11. Zeilhofer HU
    12. Watanabe M
    13. Riddell JS
    14. Todd AJ
    15. Hoon MA

    (2018) Circuit dissection of the role of somatostatin in itch and pain

    Nature Neuroscience 21:707–716.

    https://doi.org/10.1038/s41593-018-0119-z

    • PubMed
    • Google Scholar
41. 1. Ikoma A
    2. Steinhoff M
    3. Ständer S
    4. Yosipovitch G
    5. Schmelz M

    (2006) The neurobiology of itch

    Nature Reviews Neuroscience 7:535–547.

    https://doi.org/10.1038/nrn1950

    • PubMed
    • Google Scholar
42. 1. Ioannidis LJ
    2. Nie CQ
    3. Ly A
    4. Ryg-Cornejo V
    5. Chiu CY
    6. Hansen DS

    (2016) Monocyte- and Neutrophil-Derived CXCL10 impairs efficient control of Blood-Stage malaria infection and promotes severe disease

    The Journal of Immunology 196:1227–1238.

    https://doi.org/10.4049/jimmunol.1501562

    • PubMed
    • Google Scholar
43. 1. Jabbari A
    2. Suárez-Fariñas M
    3. Dewell S
    4. Krueger JG

    (2012) Transcriptional profiling of psoriasis using RNA-seq reveals previously unidentified differentially expressed genes

    Journal of Investigative Dermatology 132:246–249.

    https://doi.org/10.1038/jid.2011.267

    • PubMed
    • Google Scholar
44. 1. Jing PB
    2. Cao DL
    3. Li SS
    4. Zhu M
    5. Bai XQ
    6. Wu XB
    7. Gao YJ

    (2018) Chemokine receptor CXCR3 in the spinal cord contributes to chronic itch in mice

    Neuroscience Bulletin 34:54–63.

    https://doi.org/10.1007/s12264-017-0128-z

    • PubMed
    • Google Scholar
45. 1. Kamo A
    2. Tominaga M
    3. Taneda K
    4. Ogawa H
    5. Takamori K

    (2013) Neurotropin inhibits the increase in intraepidermal nerve density in the acetone-treated dry-skin mouse model

    Clinical and Experimental Dermatology 38:665–668.

    https://doi.org/10.1111/ced.12100

    • PubMed
    • Google Scholar
46. 1. Kanda N
    2. Shimizu T
    3. Tada Y
    4. Watanabe S

    (2007) IL-18 enhances IFN-gamma-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes

    European Journal of Immunology 37:338–350.

    https://doi.org/10.1002/eji.200636420

    • PubMed
    • Google Scholar
47. 1. Kim BS
    2. Siracusa MC
    3. Saenz SA
    4. Noti M
    5. Monticelli LA
    6. Sonnenberg GF
    7. Hepworth MR
    8. Van Voorhees AS
    9. Comeau MR
    10. Artis D

    (2013) TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation

    Science Translational Medicine 5:170ra16.

    https://doi.org/10.1126/scitranslmed.3005374

    • PubMed
    • Google Scholar
48. 1. Kim D
    2. Kobayashi T
    3. Nagao K

    (2019) Research techniques made simple: mouse models of atopic dermatitis

    Journal of Investigative Dermatology 139:984–990.

    https://doi.org/10.1016/j.jid.2019.02.014

    • PubMed
    • Google Scholar
49. 1. Kitamura A
    2. Takata R
    3. Aizawa S
    4. Watanabe H
    5. Wada T

    (2018) A murine model of atopic dermatitis can be generated by painting the dorsal skin with hapten twice 14 days apart

    Scientific Reports 8:1–9.

    https://doi.org/10.1038/s41598-018-24363-6

    • Google Scholar
50. 1. Koga C
    2. Kabashima K
    3. Shiraishi N
    4. Kobayashi M
    5. Tokura Y

    (2008) Possible pathogenic role of Th17 cells for atopic dermatitis

    Journal of Investigative Dermatology 128:2625–2630.

    https://doi.org/10.1038/jid.2008.111

    • PubMed
    • Google Scholar
51. 1. Koro O
    2. Furutani K
    3. Hide M
    4. Yamada S
    5. Yamamoto S

    (1999) Chemical mediators in atopic dermatitis: involvement of leukotriene B4 released by a type I allergic reaction in the pathogenesis of atopic dermatitis

    Journal of Allergy and Clinical Immunology 103:663–670.

    https://doi.org/10.1016/S0091-6749(99)70240-X

    • PubMed
    • Google Scholar
52. 1. Kou K
    2. Nakamura F
    3. Aihara M
    4. Chen H
    5. Seto K
    6. Komori-Yamaguchi J
    7. Kambara T
    8. Nagashima Y
    9. Goshima Y
    10. Ikezawa Z

    (2012) Decreased expression of semaphorin-3A, a neurite-collapsing factor, is associated with itch in psoriatic skin

    Acta Dermato Venereologica 92:521–528.

    https://doi.org/10.2340/00015555-1350

    • PubMed
    • Google Scholar
53. 1. Langmead B
    2. Trapnell C
    3. Pop M
    4. Salzberg SL

    (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome

    Genome Biology 10:R25.

    https://doi.org/10.1186/gb-2009-10-3-r25

    • Google Scholar
54. 1. Langmead B
    2. Salzberg SL

    (2012) Fast gapped-read alignment with bowtie 2

    Nature Methods 9:357–359.

    https://doi.org/10.1038/nmeth.1923

    • PubMed
    • Google Scholar
55. 1. Levine JD
    2. Khasar SG
    3. Green PG

    (2006) Neurogenic inflammation and arthritis

    Annals of the New York Academy of Sciences 1069:155–167.

    https://doi.org/10.1196/annals.1351.014

    • PubMed
    • Google Scholar
56. 1. Li M
    2. Hener P
    3. Zhang Z
    4. Kato S
    5. Metzger D
    6. Chambon P

    (2006) Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis

    PNAS 103:11736–11741.

    https://doi.org/10.1073/pnas.0604575103

    • PubMed
    • Google Scholar
57. 1. Li M
    2. Hener P
    3. Zhang Z
    4. Ganti KP
    5. Metzger D
    6. Chambon P

    (2009) Induction of thymic stromal lymphopoietin expression in keratinocytes is necessary for generating an atopic dermatitis upon application of the active vitamin D3 analogue MC903 on mouse skin

    Journal of Investigative Dermatology 129:498–502.

    https://doi.org/10.1038/jid.2008.232

    • PubMed
    • Google Scholar
58. 1. Li C
    2. Maillet I
    3. Mackowiak C
    4. Viala C
    5. Di Padova F
    6. Li M
    7. Togbe D
    8. Quesniaux V
    9. Lai Y
    10. Ryffel B

    (2017) Experimental atopic dermatitis depends on IL-33R signaling via MyD88 in dendritic cells

    Cell Death & Disease 8:e2735.

    https://doi.org/10.1038/cddis.2017.90

    • PubMed
    • Google Scholar
59. 1. Liu B
    2. Tai Y
    3. Achanta S
    4. Kaelberer MM
    5. Caceres AI
    6. Shao X
    7. Fang J
    8. Jordt SE

    (2016) IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

    PNAS 113:E7572–E7579.

    https://doi.org/10.1073/pnas.1606608113

    • PubMed
    • Google Scholar
60. 1. Liu B
    2. Tai Y
    3. Liu B
    4. Caceres AI
    5. Yin C
    6. Jordt S-E

    (2019) Transcriptome profiling reveals Th2 Bias and identifies endogenous itch mediators in poison ivy contact dermatitis

    JCI Insight 4:e124497.

    https://doi.org/10.1172/jci.insight.124497

    • Google Scholar
61. 1. Liu T
    2. Ji RR

    (2012) Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice

    Neuroscience Bulletin 28:145–154.

    https://doi.org/10.1007/s12264-012-1207-9

    • PubMed
    • Google Scholar
62. 1. Malik K
    2. Ungar B
    3. Garcet S
    4. Dutt R
    5. Dickstein D
    6. Zheng X
    7. Xu H
    8. Estrada YD
    9. Suárez-Fariñas M
    10. Shemer A
    11. Krueger JG
    12. Guttman-Yassky E

    (2017) Dust mite induces multiple polar T cell axes in human skin

    Clinical & Experimental Allergy 47:1648–1660.

    https://doi.org/10.1111/cea.13040

    • PubMed
    • Google Scholar
63. 1. Mansouri Y
    2. Guttman-Yassky E

    (2015) Immune pathways in atopic dermatitis, and definition of biomarkers through broad and targeted therapeutics

    Journal of Clinical Medicine 4:858–873.

    https://doi.org/10.3390/jcm4050858

    • PubMed
    • Google Scholar
64. 1. Marshall KL
    2. Clary RC
    3. Baba Y
    4. Orlowsky RL
    5. Gerling GJ
    6. Lumpkin EA

    (2016) Touch receptors undergo rapid remodeling in healthy skin

    Cell Reports 17:1719–1727.

    https://doi.org/10.1016/j.celrep.2016.10.034

    • PubMed
    • Google Scholar
65. 1. Martel BC
    2. Lovato P
    3. Bäumer W
    4. Olivry T

    (2017)

    Translational animal models of atopic dermatitis for preclinical studies

    The Yale Journal of Biology and Medicine 90:389–402.

    • PubMed
    • Google Scholar
66. 1. Matterne U
    2. Apfelbacher CJ
    3. Loerbroks A
    4. Schwarzer T
    5. Büttner M
    6. Ofenloch R
    7. Diepgen TL
    8. Weisshaar E

    (2011) Prevalence, correlates and characteristics of chronic pruritus: a population-based cross-sectional study

    Acta Dermato Venereologica 91:674–679.

    https://doi.org/10.2340/00015555-1159

    • PubMed
    • Google Scholar
67. 1. Meixiong J
    2. Anderson M
    3. Limjunyawong N
    4. Sabbagh MF
    5. Hu E
    6. Mack MR
    7. Oetjen LK
    8. Wang F
    9. Kim BS
    10. Dong X

    (2019) Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled receptors drives Non-histaminergic itch

    Immunity 50:1163–1171.

    https://doi.org/10.1016/j.immuni.2019.03.013

    • PubMed
    • Google Scholar
68. 1. Meng J
    2. Moriyama M
    3. Feld M
    4. Buddenkotte J
    5. Buhl T
    6. Szöllösi A
    7. Zhang J
    8. Miller P
    9. Ghetti A
    10. Fischer M
    11. Reeh PW
    12. Shan C
    13. Wang J
    14. Steinhoff M

    (2018) New mechanism underlying IL-31-induced atopic dermatitis

    Journal of Allergy and Clinical Immunology 141:1677–1689.

    https://doi.org/10.1016/j.jaci.2017.12.1002

    • PubMed
    • Google Scholar
69. 1. Michalec L
    2. Choudhury BK
    3. Postlethwait E
    4. Wild JS
    5. Alam R
    6. Lett-Brown M
    7. Sur S

    (2002) CCL7 and CXCL10 orchestrate oxidative stress-induced neutrophilic lung inflammation

    The Journal of Immunology 168:846–852.

    https://doi.org/10.4049/jimmunol.168.2.846

    • PubMed
    • Google Scholar
70. 1. Mihm MC
    2. Soter NA
    3. Dvorak HF
    4. Austen KF

    (1976) The structure of normal skin and the morphology of atopic eczema

    Journal of Investigative Dermatology 67:305–312.

    https://doi.org/10.1111/1523-1747.ep12514346

    • PubMed
    • Google Scholar
71. 1. Mollanazar NK
    2. Smith PK
    3. Yosipovitch G

    (2016) Mediators of chronic pruritus in atopic dermatitis: getting the itch out?

    Clinical Reviews in Allergy & Immunology 51:263–292.

    https://doi.org/10.1007/s12016-015-8488-5

    • PubMed
    • Google Scholar
72. 1. Moosbrugger-Martinz V
    2. Schmuth M
    3. Dubrac S

    (2017) A mouse model for atopic dermatitis using topical application of vitamin D3 or of its analog MC903

    Methods in Molecular Biology 1559:91–106.

    https://doi.org/10.1007/978-1-4939-6786-5_8

    • PubMed
    • Google Scholar
73. 1. Morita T
    2. McClain SP
    3. Batia LM
    4. Pellegrino M
    5. Wilson SR
    6. Kienzler MA
    7. Lyman K
    8. Olsen AS
    9. Wong JF
    10. Stucky CL
    11. Brem RB
    12. Bautista DM

    (2015) HTR7 mediates serotonergic acute and chronic itch

    Neuron 87:124–138.

    https://doi.org/10.1016/j.neuron.2015.05.044

    • PubMed
    • Google Scholar
74. 1. Nattkemper LA
    2. Tey HL
    3. Valdes-Rodriguez R
    4. Lee H
    5. Mollanazar NK
    6. Albornoz C
    7. Sanders KM
    8. Yosipovitch G

    (2018) The genetics of chronic itch: gene expression in the skin of patients with atopic dermatitis and psoriasis with severe Itch

    Journal of Investigative Dermatology 138:1311–1317.

    https://doi.org/10.1016/j.jid.2017.12.029

    • PubMed
    • Google Scholar
75. 1. Oaklander AL

    (2011) Neuropathic itch

    Seminars in Cutaneous Medicine and Surgery 30:87–92.

    https://doi.org/10.1016/j.sder.2011.04.006

    • PubMed
    • Google Scholar
76. 1. Oaklander AL
    2. Siegel SM

    (2005) Cutaneous innervation: form and function

    Journal of the American Academy of Dermatology 53:1027–1037.

    https://doi.org/10.1016/j.jaad.2005.08.049

    • PubMed
    • Google Scholar
77. 1. Oetjen LK
    2. Mack MR
    3. Feng J
    4. Whelan TM
    5. Niu H
    6. Guo CJ
    7. Chen S
    8. Trier AM
    9. Xu AZ
    10. Tripathi SV
    11. Luo J
    12. Gao X
    13. Yang L
    14. Hamilton SL
    15. Wang PL
    16. Brestoff JR
    17. Council ML
    18. Brasington R
    19. Schaffer A
    20. Brombacher F
    21. Hsieh CS
    22. Gereau RW
    23. Miller MJ
    24. Chen ZF
    25. Hu H
    26. Davidson S
    27. Liu Q
    28. Kim BS

    (2017) Sensory neurons Co-opt classical immune signaling pathways to mediate chronic itch

    Cell 171:217–228.

    https://doi.org/10.1016/j.cell.2017.08.006

    • PubMed
    • Google Scholar
78. 1. Oetjen LK
    2. Kim BS

    (2018) Interactions of the immune and sensory nervous systems in atopy

    The FEBS Journal 285:3138–3151.

    https://doi.org/10.1111/febs.14465

    • PubMed
    • Google Scholar
79. 1. Oyoshi MK
    2. He R
    3. Li Y
    4. Mondal S
    5. Yoon J
    6. Afshar R
    7. Chen M
    8. Lee DM
    9. Luo HR
    10. Luster AD
    11. Cho JS
    12. Miller LS
    13. Larson A
    14. Murphy GF
    15. Geha RS

    (2012) Leukotriene B4-driven neutrophil recruitment to the skin is essential for allergic skin inflammation

    Immunity 37:747–758.

    https://doi.org/10.1016/j.immuni.2012.06.018

    • PubMed
    • Google Scholar
80. 1. Padovan E
    2. Spagnoli GC
    3. Ferrantini M
    4. Heberer M

    (2002)

    IFN-a2a induces IP-10/CXCL10 and MIG/CXCL9 production in monocyte-derived dendritic cells and enhances their capacity to attract and stimulate CD8+ effector T cells

    Journal of Leukocyte Biology 71:669–676.

    • PubMed
    • Google Scholar
81. 1. Palmer CN
    2. Irvine AD
    3. Terron-Kwiatkowski A
    4. Zhao Y
    5. Liao H
    6. Lee SP
    7. Goudie DR
    8. Sandilands A
    9. Campbell LE
    10. Smith FJ
    11. O'Regan GM
    12. Watson RM
    13. Cecil JE
    14. Bale SJ
    15. Compton JG
    16. DiGiovanna JJ
    17. Fleckman P
    18. Lewis-Jones S
    19. Arseculeratne G
    20. Sergeant A
    21. Munro CS
    22. El Houate B
    23. McElreavey K
    24. Halkjaer LB
    25. Bisgaard H
    26. Mukhopadhyay S
    27. McLean WH

    (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

    Nature Genetics 38:441–446.

    https://doi.org/10.1038/ng1767

    • PubMed
    • Google Scholar
82. 1. Pereira MP
    2. Mühl S
    3. Pogatzki-Zahn EM
    4. Agelopoulos K
    5. Ständer S

    (2016) Intraepidermal nerve fiber density: diagnostic and therapeutic relevance in the management of chronic pruritus: a review

    Dermatology and Therapy 6:509–517.

    https://doi.org/10.1007/s13555-016-0146-1

    • Google Scholar
83. 1. Perkins NM
    2. Tracey DJ

    (2000) Hyperalgesia due to nerve injury: role of neutrophils

    Neuroscience 101:745–757.

    https://doi.org/10.1016/S0306-4522(00)00396-1

    • PubMed
    • Google Scholar
84. 1. Pinho-Ribeiro FA
    2. Verri WA
    3. Chiu IM

    (2017) Nociceptor sensory Neuron-Immune interactions in pain and inflammation

    Trends in Immunology 38:5–19.

    https://doi.org/10.1016/j.it.2016.10.001

    • PubMed
    • Google Scholar
85. 1. Pinho-Ribeiro FA
    2. Baddal B
    3. Haarsma R
    4. O'Seaghdha M
    5. Yang NJ
    6. Blake KJ
    7. Portley M
    8. Verri WA
    9. Dale JB
    10. Wessels MR
    11. Chiu IM

    (2018) Blocking neuronal signaling to immune cells treats streptococcal invasive infection

    Cell 173:1083–1097.

    https://doi.org/10.1016/j.cell.2018.04.006

    • PubMed
    • Google Scholar
86. 1. Qu L
    2. Fu K
    3. Yang J
    4. Shimada SG
    5. LaMotte RH

    (2015) CXCR3 chemokine receptor signaling mediates itch in experimental allergic contact dermatitis

    Pain 156:1737–1746.

    https://doi.org/10.1097/j.pain.0000000000000208

    • PubMed
    • Google Scholar
87. 1. Qu L
    2. Fu K
    3. Shimada SG
    4. LaMotte RH

    (2017) Cl^- channel is required for CXCL10^-induced neuronal activation and itch response in a murine model of allergic contact dermatitis

    Journal of Neurophysiology 118:619–624.

    https://doi.org/10.1152/jn.00187.2017

    • PubMed
    • Google Scholar
88. 1. Rattenholl A
    2. Steinhoff M

    (2003) Role of proteinase-activated receptors in cutaneous biology and disease

    Drug Development Research 59:408–416.

    https://doi.org/10.1002/ddr.10311

    • Google Scholar
89. 1. Salvemini D
    2. Little JW
    3. Doyle T
    4. Neumann WL

    (2011) Roles of reactive oxygen and nitrogen species in pain

    Free Radical Biology and Medicine 51:951–966.

    https://doi.org/10.1016/j.freeradbiomed.2011.01.026

    • PubMed
    • Google Scholar
90. 1. Sandilands A
    2. Terron-Kwiatkowski A
    3. Hull PR
    4. O'Regan GM
    5. Clayton TH
    6. Watson RM
    7. Carrick T
    8. Evans AT
    9. Liao H
    10. Zhao Y
    11. Campbell LE
    12. Schmuth M
    13. Gruber R
    14. Janecke AR
    15. Elias PM
    16. van Steensel MA
    17. Nagtzaam I
    18. van Geel M
    19. Steijlen PM
    20. Munro CS
    21. Bradley DG
    22. Palmer CN
    23. Smith FJ
    24. McLean WH
    25. Irvine AD

    (2007) Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema

    Nature Genetics 39:650–654.

    https://doi.org/10.1038/ng2020

    • PubMed
    • Google Scholar
91. 1. Sapieha P
    2. Stahl A
    3. Chen J
    4. Seaward MR
    5. Willett KL
    6. Krah NM
    7. Dennison RJ
    8. Connor KM
    9. Aderman CM
    10. Liclican E
    11. Carughi A
    12. Perelman D
    13. Kanaoka Y
    14. Sangiovanni JP
    15. Gronert K
    16. Smith LE

    (2011) 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ω-3 polyunsaturated fatty acids

    Science Translational Medicine 3:69ra12.

    https://doi.org/10.1126/scitranslmed.3001571

    • PubMed
    • Google Scholar
92. 1. Saunders SP
    2. Moran T
    3. Floudas A
    4. Wurlod F
    5. Kaszlikowska A
    6. Salimi M
    7. Quinn EM
    8. Oliphant CJ
    9. Núñez G
    10. McManus R
    11. Hams E
    12. Irvine AD
    13. McKenzie AN
    14. Ogg GS
    15. Fallon PG

    (2016) Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity

    Journal of Allergy and Clinical Immunology 137:482–491.

    https://doi.org/10.1016/j.jaci.2015.06.045

    • PubMed
    • Google Scholar
93. 1. Schön M
    2. Denzer D
    3. Kubitza RC
    4. Ruzicka T
    5. Schön MP

    (2000) Critical role of neutrophils for the generation of psoriasiform skin lesions in flaky skin mice

    Journal of Investigative Dermatology 114:976–983.

    https://doi.org/10.1046/j.1523-1747.2000.00953.x

    • PubMed
    • Google Scholar
94. 1. Schüttenhelm BN
    2. Duraku LS
    3. Dijkstra JF
    4. Walbeehm ET
    5. Holstege JC

    (2015) Differential changes in the peptidergic and the Non-Peptidergic skin innervation in rat models for inflammation, dry skin itch, and dermatitis

    Journal of Investigative Dermatology 135:2049–2057.

    https://doi.org/10.1038/jid.2015.137

    • PubMed
    • Google Scholar
95. 1. Scott DL
    2. Wolfe F
    3. Huizinga TWJ

    (2010) Rheumatoid arthritis

    The Lancet 376:1094–1108.

    https://doi.org/10.1016/S0140-6736(10)60826-4

    • Google Scholar
96. 1. Shalit M
    2. Campbell DE
    3. von Allmen C
    4. Atkins PC
    5. Douglas SD
    6. Zweiman B

    (1987) Neutrophil activation in human inflammatory skin reactions

    Journal of Allergy and Clinical Immunology 80:87–93.

    https://doi.org/10.1016/S0091-6749(87)80196-3

    • PubMed
    • Google Scholar
97. 1. Shimada SG
    2. LaMotte RH

    (2008) Behavioral differentiation between itch and pain in mouse

    Pain 139:681–687.

    https://doi.org/10.1016/j.pain.2008.08.002

    • PubMed
    • Google Scholar
98. 1. Shiratori-Hayashi M
    2. Koga K
    3. Tozaki-Saitoh H
    4. Kohro Y
    5. Toyonaga H
    6. Yamaguchi C
    7. Hasegawa A
    8. Nakahara T
    9. Hachisuka J
    10. Akira S
    11. Okano H
    12. Furue M
    13. Inoue K
    14. Tsuda M

    (2015) STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch

    Nature Medicine 21:927–931.

    https://doi.org/10.1038/nm.3912

    • PubMed
    • Google Scholar
99. 1. Simpson EL
    2. Bieber T
    3. Guttman-Yassky E
    4. Beck LA
    5. Blauvelt A
    6. Cork MJ
    7. Silverberg JI
    8. Deleuran M
    9. Kataoka Y
    10. Lacour JP
    11. Kingo K
    12. Worm M
    13. Poulin Y
    14. Wollenberg A
    15. Soo Y
    16. Graham NM
    17. Pirozzi G
    18. Akinlade B
    19. Staudinger H
    20. Mastey V
    21. Eckert L
    22. Gadkari A
    23. Stahl N
    24. Yancopoulos GD
    25. Ardeleanu M
    26. SOLO 1 and SOLO 2 Investigators

    (2016) Two phase 3 trials of dupilumab versus placebo in atopic dermatitis

    New England Journal of Medicine 375:2335–2348.

    https://doi.org/10.1056/NEJMoa1610020

    • PubMed
    • Google Scholar
100. 1. Sivick KE
     2. Arpaia N
     3. Reiner GL
     4. Lee BL
     5. Russell BR
     6. Barton GM

     (2014) Toll-like receptor-deficient mice reveal how innate immune signaling influences Salmonella virulence strategies

     Cell Host & Microbe 15:203–213.

     https://doi.org/10.1016/j.chom.2014.01.013

     • PubMed
     • Google Scholar
101. 1. Solinski HJ
     2. Dranchak P
     3. Oliphant E
     4. Gu X
     5. Earnest TW
     6. Braisted J
     7. Inglese J
     8. Hoon MA

     (2019a) Inhibition of natriuretic peptide receptor 1 reduces itch in mice

     Science Translational Medicine 11:eaav5464.

     https://doi.org/10.1126/scitranslmed.aav5464

     • PubMed
     • Google Scholar
102. 1. Solinski HJ
     2. Kriegbaum MC
     3. Tseng PY
     4. Earnest TW
     5. Gu X
     6. Barik A
     7. Chesler AT
     8. Hoon MA

     (2019b) Nppb neurons are sensors of mast Cell-Induced itch

     Cell Reports 26:3561–3573.

     https://doi.org/10.1016/j.celrep.2019.02.089

     • PubMed
     • Google Scholar
103. 1. Spergel JM
     2. Paller AS

     (2003) Atopic dermatitis and the atopic march

     Journal of Allergy and Clinical Immunology 112:S118–S127.

     https://doi.org/10.1016/j.jaci.2003.09.033

     • PubMed
     • Google Scholar
104. 1. Ständer S
     2. Steinhoff M

     (2002) Pathophysiology of pruritus in atopic dermatitis: an overview

     Experimental Dermatology 11:12–24.

     https://doi.org/10.1034/j.1600-0625.2002.110102.x

     • PubMed
     • Google Scholar
105. 1. Suárez-Fariñas M
     2. Dhingra N
     3. Gittler J
     4. Shemer A
     5. Cardinale I
     6. de Guzman Strong C
     7. Krueger JG
     8. Guttman-Yassky E

     (2013) Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis

     Journal of Allergy and Clinical Immunology 132:361–370.

     https://doi.org/10.1016/j.jaci.2013.04.046

     • PubMed
     • Google Scholar
106. 1. Sumida H
     2. Yanagida K
     3. Kita Y
     4. Abe J
     5. Matsushima K
     6. Nakamura M
     7. Ishii S
     8. Sato S
     9. Shimizu T

     (2014) Interplay between CXCR2 and BLT1 facilitates neutrophil infiltration and resultant keratinocyte activation in a murine model of imiquimod-induced psoriasis

     The Journal of Immunology 192:4361–4369.

     https://doi.org/10.4049/jimmunol.1302959

     • PubMed
     • Google Scholar
107. 1. Takeda M
     2. Takahashi M
     3. Matsumoto S

     (2009) Contribution of the activation of satellite Glia in sensory ganglia to pathological pain

     Neuroscience & Biobehavioral Reviews 33:784–792.

     https://doi.org/10.1016/j.neubiorev.2008.12.005

     • Google Scholar
108. 1. Tamassia N
     2. Calzetti F
     3. Ear T
     4. Cloutier A
     5. Gasperini S
     6. Bazzoni F
     7. McDonald PP
     8. Cassatella MA

     (2007) Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN-gamma in human neutrophils

     European Journal of Immunology 37:2627–2634.

     https://doi.org/10.1002/eji.200737340

     • PubMed
     • Google Scholar
109. 1. Tominaga M
     2. Ozawa S
     3. Ogawa H
     4. Takamori K

     (2007) A hypothetical mechanism of intraepidermal neurite formation in NC/Nga mice with atopic dermatitis

     Journal of Dermatological Science 46:199–210.

     https://doi.org/10.1016/j.jdermsci.2007.02.002

     • PubMed
     • Google Scholar
110. 1. Tominaga M
     2. Tengara S
     3. Kamo A
     4. Ogawa H
     5. Takamori K

     (2009) Psoralen-ultraviolet A therapy alters epidermal Sema3A and NGF levels and modulates epidermal innervation in atopic dermatitis

     Journal of Dermatological Science 55:40–46.

     https://doi.org/10.1016/j.jdermsci.2009.03.007

     • PubMed
     • Google Scholar
111. 1. Tominaga M
     2. Takamori K

     (2013) An update on peripheral mechanisms and treatments of itch

     Biological and Pharmaceutical Bulletin 36:1241–1247.

     https://doi.org/10.1248/bpb.b13-00319

     • PubMed
     • Google Scholar
112. 1. Tominaga M
     2. Takamori K

     (2014) Itch and nerve fibers with special reference to atopic dermatitis: therapeutic implications

     The Journal of Dermatology 41:205–212.

     https://doi.org/10.1111/1346-8138.12317

     • Google Scholar
113. 1. Usoskin D
     2. Furlan A
     3. Islam S
     4. Abdo H
     5. Lönnerberg P
     6. Lou D
     7. Hjerling-Leffler J
     8. Haeggström J
     9. Kharchenko O
     10. Kharchenko PV
     11. Linnarsson S
     12. Ernfors P

     (2015) Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing

     Nature Neuroscience 18:145–153.

     https://doi.org/10.1038/nn.3881

     • PubMed
     • Google Scholar
114. 1. von Moltke J
     2. Trinidad NJ
     3. Moayeri M
     4. Kintzer AF
     5. Wang SB
     6. van Rooijen N
     7. Brown CR
     8. Krantz BA
     9. Leppla SH
     10. Gronert K
     11. Vance RE

     (2012) Rapid induction of inflammatory lipid mediators by the inflammasome in vivo

     Nature 490:107–111.

     https://doi.org/10.1038/nature11351

     • Google Scholar
115. 1. Wang J

     (2018) Neutrophils in tissue injury and repair

     Cell and Tissue Research 371:531–539.

     https://doi.org/10.1007/s00441-017-2785-7

     • Google Scholar
116. 1. Wilson SR
     2. Gerhold KA
     3. Bifolck-Fisher A
     4. Liu Q
     5. Patel KN
     6. Dong X
     7. Bautista DM

     (2011) TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch

     Nature Neuroscience 14:595–602.

     https://doi.org/10.1038/nn.2789

     • PubMed
     • Google Scholar
117. 1. Yellin M
     2. Paliienko I
     3. Balanescu A
     4. Ter-Vartanian S
     5. Tseluyko V
     6. Xu LA
     7. Tao X
     8. Cardarelli PM
     9. Leblanc H
     10. Nichol G
     11. Ancuta C
     12. Chirieac R
     13. Luo A

     (2012) A phase II, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of MDX-1100, a fully human anti-CXCL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis

     Arthritis & Rheumatism 64:1730–1739.

     https://doi.org/10.1002/art.34330

     • PubMed
     • Google Scholar
118. 1. Yosipovitch G

     (2004) Dry skin and impairment of barrier function associated with itch - new insights

     International Journal of Cosmetic Science 26:1–7.

     https://doi.org/10.1111/j.0142-5463.2004.00199.x

     • PubMed
     • Google Scholar
119. 1. Yosipovitch G
     2. Papoiu AD

     (2008) What causes itch in atopic dermatitis?

     Current Allergy and Asthma Reports 8:306–311.

     https://doi.org/10.1007/s11882-008-0049-z

     • PubMed
     • Google Scholar
120. 1. Zhang Z
     2. Hener P
     3. Frossard N
     4. Kato S
     5. Metzger D
     6. Li M
     7. Chambon P

     (2009) Thymic stromal lymphopoietin overproduced by keratinocytes in mouse skin aggravates experimental asthma

     PNAS 106:1536–1541.

     https://doi.org/10.1073/pnas.0812668106

     • PubMed
     • Google Scholar
121. 1. Zhang Y
     2. Yan J
     3. Hu R
     4. Sun Y
     5. Ma Y
     6. Chen Z
     7. Jiang H

     (2015) Microglia are involved in Pruritus induced by DNFB via the CX3CR1/p38 MAPK pathway

     Cellular Physiology and Biochemistry 35:1023–1033.

     https://doi.org/10.1159/000373929

     • PubMed
     • Google Scholar
122. 1. Zheng T
     2. Yu J
     3. Oh MH
     4. Zhu Z

     (2011) The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma

     Allergy, Asthma and Immunology Research 3:67–73.

     https://doi.org/10.4168/aair.2011.3.2.67

     • Google Scholar

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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