Autoimmunity: Bringing on the itch
Atopic dermatitis is characterized by debilitating chronic itch and affects about 12% of children and 7% of adults in the United States (Silverberg, 2017). Most itching is harmless, and it can act as a defense mechanism when it triggers scratching behaviors that remove macroscopic parasites or harmful substances from the skin. But the itch associated with atopic dermatitis is far from harmless, being linked to loss of sleep, reduced quality of life and psychiatric symptoms (Chiesa Fuxench et al., 2019).
To date, the most successful treatment for atopic dermatitis is dupilumab, an antibody that regulates two signaling pathways (the IL-4 and IL-13 pathways) by binding to a receptor called IL-4Ra. In clinical trials of adult patients with moderate-to-severe atopic dermatitis, approximately half showed a reduction in the severity of the itch after a year of dupilumab injections and treatment with corticosteroids (Blauvelt et al., 2017). While this confirms that IL-4Ra has a role in causing the itch associated with atopic dermatitis, the fact that a significant number of patients did not respond to treatment makes it clear that our understanding of this condition is far from complete. Now, in eLife, Diana Bautista (University of California, Berkeley) and colleagues – including Carolyn Walsh and Rose Hill as joint first authors – report that white blood cells called neutrophils also have a central role in atopic dermatitis (Walsh et al., 2019).
Walsh et al. exposed mice to calcipotriol, a chemical that induces symptoms similar to human atopic dermatitis, and analyzed its effect on the behavior of the mice, and also its effect at the cellular and molecular level. Calcipotriol is known to induce the production of TSLP, a cytokine that activates several types of immune cells (including CD4+ T cells, eosinophils and mast cells). These cells are commonly associated with itch, which leads to scratching behavior in mice (Li et al., 2006; Yoo et al., 2005; Mack and Kim, 2018).
The experiments of Walsh et al. showed that neutrophils infiltrated the exposure site before any of the other immune cells associated with the response to TSLP. Neutrophil infiltration occurred at the same time as the mice started scratching the site of calcipotriol application, a behavior that was significantly reduced when neutrophils were depleted. Furthermore, injecting a chemokine that recruits neutrophils into mice that had not been exposed to calcipotriol was sufficient to induce scratching behavior. These results indicate that neutrophils may be causing some of the itch associated with atopic dermatitis.
Next, Walsh et al. used mice that had been genetically modified to lack the TSLP receptor (TSLPR), also called TSLPR knock-out mice. When these mice were exposed to calcipotriol, fewer basophils, CD4+ T cells and mast cells were recruited to the exposure site, confirming that TSLP had a role in recruiting these itch-inducing cells. However, the knock-out mice still exhibited scratching behavior in the early stages of calcipotriol application, even though the behavior decreased significantly later on. This suggests that TSLP has a role in causing itch in later stages of atopic dermatitis, but other mechanisms must be responsible for causing itch early on. Neutrophil infiltration was not affected in TSLPR knock-out mice. These results indicate that neutrophils have an early (as well as a sustained) role in the progression of the itch associated with atopic dermatitis.
Analyzing the gene expression of mice exposed to calcipotriol showed that genes affecting how the skin acts as a barrier changed quickly after exposure, followed by alterations in neuronal and cytokine genes. The activity of some cytokine genes increased when both neutrophils and TSLPR were present, while others were upregulated independently of neutrophils but dependent on TSLPR. Yet other genes coding for cytokines such as CXCL10 depended on the presence of neutrophils but not TSLPR.
CXCL10 is a cytokine that can be produced by neutrophils and is known to signal through CXCR3 in sensory neurons to drive scratching behavior (Qu et al., 2015). Walsh et al. showed that blocking CXCR3 attenuated both the early and late scratching behavior induced by calcipotriol. Thus, early infiltration by neutrophils may induce innervation of the affected skin and sensitize the neuronal circuits responsible for scratching behavior by signaling through CXCL10 and CXCR3.
The work of Walsh et al. reveals a new mechanism contributing to the itch associated with atopic dermatitis and reinforces the concept that there are multiple drivers in this disease. Along with TSLP and IL4/IL-13, CXCL10 may cause some of the symptoms of atopic dermatitis, although the role of this cytokine in the disease remains to be fully characterized. Importantly, neutrophils and TSLP represent independent pathways in the chronic phase of calcipotriol treatment in mice (Figure 1). This suggests that a subset of human patients with atopic dermatitis may be more sensitive to TSLP, and another more sensitive to neutrophils. This neutrophil-sensitive group of patients may benefit from treatments that interfere with neutrophil activity or with the communication between neutrophils and neurons through CXCL10/CXCR3.
References
-
Atopic dermatitis in America study: A cross-sectional study examining the prevalence and disease burden of atopic dermatitis in the US adult populationJournal of Investigative Dermatology 139:583–590.https://doi.org/10.1016/j.jid.2018.08.028
-
The itch-scratch cycle: a neuroimmune perspectiveTrends in Immunology 39:980–991.https://doi.org/10.1016/j.it.2018.10.001
-
Public health burden and epidemiology of atopic dermatitisDermatologic Clinics 35:283–289.https://doi.org/10.1016/j.det.2017.02.002
-
Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skinThe Journal of Experimental Medicine 202:541–549.https://doi.org/10.1084/jem.20041503
Article and author information
Author details
Publication history
Copyright
© 2019, Waizman et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,286
- views
-
- 139
- downloads
-
- 0
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Chromosomes and Gene Expression
- Immunology and Inflammation
Genome-wide association studies (GWAS) have identified hundreds of genetic signals associated with autoimmune disease. The majority of these signals are located in non-coding regions and likely impact cis-regulatory elements (cRE). Because cRE function is dynamic across cell types and states, profiling the epigenetic status of cRE across physiological processes is necessary to characterize the molecular mechanisms by which autoimmune variants contribute to disease risk. We localized risk variants from 15 autoimmune GWAS to cRE active during TCR-CD28 co-stimulation of naïve human CD4+ T cells. To characterize how dynamic changes in gene expression correlate with cRE activity, we measured transcript levels, chromatin accessibility, and promoter–cRE contacts across three phases of naive CD4+ T cell activation using RNA-seq, ATAC-seq, and HiC. We identified ~1200 protein-coding genes physically connected to accessible disease-associated variants at 423 GWAS signals, at least one-third of which are dynamically regulated by activation. From these maps, we functionally validated a novel stretch of evolutionarily conserved intergenic enhancers whose activity is required for activation-induced IL2 gene expression in human and mouse, and is influenced by autoimmune-associated genetic variation. The set of genes implicated by this approach are enriched for genes controlling CD4+ T cell function and genes involved in human inborn errors of immunity, and we pharmacologically validated eight implicated genes as novel regulators of T cell activation. These studies directly show how autoimmune variants and the genes they regulate influence processes involved in CD4+ T cell proliferation and activation.
-
- Cell Biology
- Immunology and Inflammation
Arpin was discovered as an inhibitor of the Arp2/3 complex localized at the lamellipodial tip of fibroblasts, where it regulated migration steering. Recently, we showed that arpin stabilizes the epithelial barrier in an Arp2/3-dependent manner. However, the expression and functions of arpin in endothelial cells (EC) have not yet been described. Arpin mRNA and protein are expressed in EC and downregulated by pro-inflammatory cytokines. Arpin depletion in Human Umbilical Vein Endothelial Cells causes the formation of actomyosin stress fibers leading to increased permeability in an Arp2/3-independent manner. Instead, inhibitors of ROCK1 and ZIPK, kinases involved in the generation of stress fibers, normalize the loss-of-arpin effects on actin filaments and permeability. Arpin-deficient mice are viable but show a characteristic vascular phenotype in the lung including edema, microhemorrhage, and vascular congestion, increased F-actin levels, and vascular permeability. Our data show that, apart from being an Arp2/3 inhibitor, arpin is also a regulator of actomyosin contractility and endothelial barrier integrity.