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

Abstract

These authors contributed equally and order determined by coin toss. Abstract 1Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch 2 diseases are thought to be driven by both the nervous and immune systems, but the 3 fundamental molecular and cellular interactions that trigger the development of itch and the 4 acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils 5are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil 6 depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. 7Neutrophils were also required for several key hallmarks of chronic itch, including skin 8 hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of 9 inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we 10 demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 11 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 12 antagonism attenuates chronic itch. 13 14Introduction 15 Chronic itch is a debilitating disorder that affects millions of people worldwide. 1-3 It is a symptom 16 of a number of skin diseases and systemic disorders, as well as a side effect of a growing list of 17 medications. Like chronic pain, chronic itch can be a disease in and of itself. 4-6 Unlike acute itch, 18 which can facilitate removal of crawling insects, parasites, or irritants, persistent scratching in 19chronic itch disorders has no discernable benefit; scratching damages skin, leading to 20 secondary infection, disfiguring lesions, and exacerbation of disease severity. 2,7,8 The most 21 common chronic itch disorder is atopic dermatitis (AD; commonly known as eczema), which 22 affects fifteen million people in the United States alone. 9 Severe AD can trigger the atopic 23 march, where chronic itch and inflammation progress to food allergy, allergic rhinitis, and 24 asthma. 9,10 25 26Little is known about the underlying mechanisms that drive chronic itch pathogenesis. As such, 27 studies of human chronic itch disorders have sought to identify candidate mechanisms of 28 disease progression. A number of studies have identified biomarkers and disease genes in itchy 29 human AD lesions. [11][12][13][14][15] Indeed, a recent study compared the transcriptomes of healthy skin to 30 itchy and non-itchy skin from psoriasis and AD patients, revealing dramatic changes in 31 expression of genes associated with cytokines, immune cells, epithelial cells, and sensory 32 neurons. 16 However, due to the difficulty in staging lesion development and obtaining staged 33 samples from patients, there is currently no temporal map of when individual molecules and cell 34 types contribute to chronic itch pathogenesis. Furthermore, the use of human patient data does 35 not allow for rigorous mechanistic study of how disease genes contribute to chronic itch. To this 36 end,...

A basophil-neuronal axis promotes itch

“…Thus, we undertook a chemogenetic gainof-function approach to demonstrate that selective activation of basophils alone is sufficient to induce itch in mice. Although basophils critically promote AD-like skin inflammation (Imai et al, 2019;Kim et al, 2014a;Walsh et al, 2019), surprisingly, we found that they do not mediate chronic spontaneous itch. Furthermore, our study reveals that while mast cells and histamine are critical for acute itch in the steady state, basophils and LTC4 mediate acute itch flares in AD-like disease.…”

The role of interleukin-24 in atopic dermatitis

“…IL-24 acts as an activator of STAT3, which is also activated by IL-31 to promote elongation of the nerve fibers, followed by enhanced itching [63]. Additionally, IL-24 upregulated the expression of CXCL1 [54], a chemokine that can evoke itch through multiple pathways [64,65]. These data suggest the involvement of IL-24 in the mechanism of pruritus in AD.…”

Repeated dermal application of the common preservative methylisothiazolinone triggers local inflammation, T cell influx, and prolonged mast cell-dependent tactile sensitivity in mice

“…Eosinophils were recruited early following MI skin exposure ( Fig 1F ) and are known regulators of allergic disease and tissue remodeling [ 41 ]. We also saw MI-driven accumulation of neutrophils in the skin ( Fig 1G ); these cells are associated with psoriasis and atopic dermatitis [ 42 , 43 ]. To our knowledge, eosinophils and neutrophils have not been studied in vulvodynia or in MI contact allergy but may have important modulatory roles in both.…”