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

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Carolyn M Walsh ◽  
Rose Z Hill ◽  
Jamie Schwendinger-Schreck ◽  
Jacques Deguine ◽  
Emily C Brock ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Sensory Neurons ◽  
Treatment Options ◽  
Cellular Interactions ◽  
Immune Systems ◽  
Chronic Itch ◽  
Enhanced Expression ◽  
Neutrophil Depletion ◽  
Induced Genes ◽  
Neuropathic Itch

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.

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

2019 ◽  
Author(s):  
Carolyn M. Walsh ◽  
Rose Z. Hill ◽  
Jamie Schwendinger-Schreck ◽  
Jacques Deguine ◽  
Emily C. Brock ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Sensory Neurons ◽  
Treatment Options ◽  
Cellular Interactions ◽  
Immune Systems ◽  
Chronic Itch ◽  
Enhanced Expression ◽  
Neutrophil Depletion ◽  
Induced Genes ◽  
Neuropathic Itch

AbstractChronic 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.

scholarly journals Breaking the Itch–Scratch Cycle: Topical Options for the Management of Chronic Cutaneous Itch in Atopic Dermatitis

Medicines ◽  
2019 ◽  
Vol 6 (3) ◽  
pp. 76 ◽  
Author(s):  
Ian P. Harrison ◽  
Fabrizio Spada
Keyword(s):  
Atopic Dermatitis ◽  
Treatment Options ◽  
Calcineurin Inhibitors ◽  
Cost Of Treatment ◽  
Topical Calcineurin Inhibitors ◽  
Chronic Itch ◽  
Itch Sensation ◽  
Chronic Pruritus

Chronic itch is an unpleasant sensation that triggers a desire to scratch that lasts for six weeks or more. It is a major diagnostic symptom of myriad diseases, including atopic dermatitis for which it is the most prominent feature. Chronic itch can be hugely debilitating for the sufferer, damaging in terms of both the monetary cost of treatment and its socioeconomic effects, and few treatment options exist that can adequately control it. Corticosteroids remain the first line treatment strategy for atopic dermatitis, but due to the risks associated with long-term use of corticosteroids, and the drawbacks of other topical options such as topical calcineurin inhibitors and capsaicin, topical options for itch management that are efficacious and can be used indefinitely are needed. In this review, we detail the pathophysiology of chronic pruritus, its key features, and the disease most commonly associated with it. We also assess the role of the skin and its components in maintaining a healthy barrier function, thus reducing dryness and the itch sensation. Lastly, we briefly detail examples of topical options for the management of chronic pruritus that can be used indefinitely, overcoming the risk associated with long-term use of corticosteroids.

scholarly journals Central opioid receptors mediate morphine-induced itch and chronic itch

2020 ◽  
Author(s):  
Zilong Wang ◽  
Changyu Jiang ◽  
Hongyu Yao ◽  
Ouyang Chen ◽  
Sreya Rahman ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sensory Neurons ◽  
Common Side Effect ◽  
Cellular Mechanisms ◽  
Conditional Deletion ◽  
Outward Currents ◽  
Clinical Pain ◽  
Chronic Itch ◽  
Allergic Contact

AbstractOpioids, such as morphine are mainstay treatments for clinical pain conditions. Itch is a common side effect of opioids, particularly as a result of epidural or intrathecal (i.t.) administration. Recent progress has advanced our understanding of itch circuits in the spinal cord. However, the mechanisms underlying opioid-induced itch are not fully understood, although an interaction between µ-opioid receptor (MOR) and gastrin-releasing peptide receptor (GRPR) in spinal GRPR-expressing neurons has been implicated. In this study we investigated the cellular mechanisms of intrathecal (i.t.) opioid-induced itch by conditional deletion of MOR-encoding Oprm1 in distinct populations of interneurons and sensory neurons. We found that i.t. injection of the MOR agonists morphine or DAMGO elicited dose-dependent scratching, but this pruritus was totally abolished in mice with a specific Oprm1 deletion in Vgat+ neurons (Oprm1-Vgat). Loss of MOR in somatostatin+ interneurons and TRPV1+ sensory neurons did not affect morphine-induced itch but impaired morphine-induced antinociception. In situ hybridization revealed Oprm1 expression in 30% of inhibitory and 20% of excitatory interneurons in the spinal dorsal horn. Whole-cell recordings from spinal cord slices showed that DAMGO induced outward currents in 9 out of 19 Vgat+ interneurons examined. Morphine also inhibited action potentials in Vgat+ interneurons and suppressed evoked IPSCs in postsynaptic Vgat- excitatory neurons, suggesting a mechanism of disinhibition by MOR agonists. Notably, morphine-elicited itch was suppressed by i.t. administration of NPY and abolished by spinal ablation of GRPR+ neurons, whereas i.t. GRP-induced itch response remained intact in mice lacking Oprm1-Vgat. Additionally, chronic itch from DNFB-induced allergic contact dermatitis was decreased by Oprm1-Vgat deletion. Finally, naloxone, but not peripherally restricted naloxone methiodide, inhibited chronic itch in the DNFB model and the cutaneous T-cell lymphoma (CTCL) model, indicating a contribution of central MOR signaling to chronic itch. Our findings demonstrate that i.t. morphine elicits itch via acting on MOR on spinal inhibitory interneurons, leading to disinhibition of the spinal itch circuit. Our data also suggest that chronic itch could be effectively treated with CNS-targeted naloxone.

scholarly journals Molecular signature of pruriceptive MrgprA3+ neurons

2019 ◽  
Author(s):  
Yanyan Xing ◽  
Junyu Chen ◽  
Henry Hilley ◽  
Haley Steele ◽  
Jingjing Yang ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Molecular Mechanisms ◽  
Molecular Signature ◽  
Neuronal Populations ◽  
Pathological Conditions ◽  
Chronic Itch ◽  
Itch Sensation ◽  
Profile Changes ◽  
Allergic Contact

ABSTRACTItch, initiated by the activation of sensory neurons, is frequently associated with dermatological or systemic diseases and significantly affects patient quality of life. MrgprA3+ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulations of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here we performed RNA sequencing of genetically labeled MrgprA3+ neurons under both naïve and allergic contact dermatitis condition. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3+ neurons, suggesting that MrgprA3+ neurons are the main, direct neuronal target for histamine and Mrgprs agonists. In addition, Ptpn6 and Pcdh12 were identified as novel and highly selective markers of MrgprA3+ neurons. We also discovered that MrgprA3+ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potentially novel targets for combating itch.

scholarly journals 365 The genetics of chronic itch: Correlating itch severity to gene expression in the skin of atopic dermatitis and psoriasis patients

2016 ◽  
Vol 136 (5) ◽  
pp. S65
Author(s):  
L.A. Nattkemper ◽  
R. Valdes-Rodriguez ◽  
H.G. Lee ◽  
N.K. Mollanazar ◽  
C. Albornoz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Atopic Dermatitis ◽  
Chronic Itch

Basophils getting on your nerves? Itching for clarity on flares in atopic dermatitis

2021 ◽  
Vol 6 (56) ◽  
pp. eabg8047
Author(s):  
Sarah E. Henrickson
Keyword(s):  
Atopic Dermatitis ◽  
Sensory Neurons ◽  
Neuroimmune Axis

Flares of acute itch in the setting of atopic dermatitis may engage a novel neuroimmune axis that includes basophils, LTC4, and sensory neurons.

scholarly journals Approach to the Assessment and Management of Pediatric Patients With Atopic Dermatitis: A Consensus Document. Section III: Treatment Options for Pediatric Atopic Dermatitis

2019 ◽  
Vol 23 (5_suppl) ◽  
pp. 19S-31S
Author(s):  
Perla Lansang ◽  
Joseph M. Lam ◽  
Danielle Marcoux ◽  
Vimal H. Prajapati ◽  
Shanna Spring ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Maintenance Therapy ◽  
Pediatric Patients ◽  
Treatment Options ◽  
Skin Barrier ◽  
Active Therapy ◽  
Disease Treatment ◽  
Consensus Document ◽  
Emerging Therapies ◽  
Clinical Considerations

Because atopic dermatitis (AD) is a chronic, relapsing disease, treatment requires the use of both active therapy to control flares and preventative maintenance therapy to promote integrity of the skin barrier. In this third of four sections, important clinical considerations for the treatment of pediatric AD are reviewed. Emerging therapies in development for pediatric AD are introduced.

Sign in / Sign up

Export Citation Format

Share Document