Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the development of itch and the acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. Neutrophils were also required for several key hallmarks of chronic itch, including skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 antagonism attenuates chronic itch.

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,...

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Purpose of Review Massive irreparable rotator cuff tears present a significant challenge to the orthopedic surgeon. No single treatment, particularly among joint-preserving options, has been shown to be superior. The purpose of this review is to discuss recent advances in the treatment of massive irreparable rotator cuff tears, including partial repair with and without graft augmentation, interposition grafts, superior capsule reconstruction, subacromial balloon spacers, tendon transfer, and reverse total shoulder arthroplasty. We will also offer guidance on surgical indications based on our clinical experience. Recent Findings Partial repair may offer reasonable clinical improvement for patients with lower preoperative function despite high re-tear rates. Additionally, several types of interposition grafts have shown promising short-term results and may outperform repair alone. Subacromial balloon spacers may lead to clinical improvement, especially in patients without glenohumeral osteoarthritis or pseudoparalysis, and recently received FDA approval for use in the USA. Superior capsule reconstruction is a technically demanding procedure that appears to produce excellent short-term results particularly when performed at high volume, but long-term studies in heterogeneous study groups are needed. Tendon transfers improve function by restoring force coupling in the shoulder, offering a promising option for younger patients. Reverse total shoulder arthroplasty (RTSA) is a reliable option for treatment of irreparable cuff tears in elderly patients with lower functional demands. Summary Irreparable cuff tears remain a difficult condition to treat. Recommended treatment for younger patients without glenohumeral osteoarthritis is particularly controversial. For older patients with low-demand lifestyles and glenohumeral osteoarthritis, RTSA is an effective treatment option. For all discussed procedures, patient selection appears to play a critical role in clinical outcomes.

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