Sensory neuroimmune interactions at the barrier.

Epithelial barriers such as the skin, lung, and gut, in addition to having unique physiologic functions, are designed to preserve tissue homeostasis upon challenge with a variety of allergens, irritants, or pathogens. Both the innate and adaptive immune systems play a critical role in responding to epithelial cues triggered by environmental stimuli. However, the mechanisms by which organs sense and coordinate complex epithelial, stromal, and immune responses have remained a mystery. Our increasing understanding of the anatomic and functional characteristics of the sensory nervous system is greatly advancing a new field of peripheral neuroimmunology and subsequently changing our understanding of mucosal immunology. Herein, we detail how sensory biology is informing mucosal neuroimmunology, even beyond neuroimmune interactions seen within the central and autonomic nervous systems.

Botanical oleander extract and oleandrin have superior effects on innate immune functions pertaining to dermal allergic reactions in canine cells when compared to oclacitinib.

OBJECTIVE: To perform testing for cytokines involved in dermal inflammatory reactions and to document and compare the effects of an oleander extract (OE), oleandrin, and oclacitinib on biomarkers relevant to allergic reactions. The effects of these compounds under inflamed culture conditions are of direct importance to the treatment of canine atopic dermatitis. METHODS: Testing involved primary canine dermal fibroblasts and the canine DH82 macrophage cell line; both cell types are important for initiating, regulating, and resolving dermal allergic reactions via cytokine communication. RESULTS: Under inflamed conditions, OE and oleandrin downregulated key cytokines secreted by canine dermal fibroblasts and the DH82 macrophage cell line; all of which are treatment targets in dermatitis. In the DH82 macrophage cultures, the most noteworthy reductions involved IL-6, IL-12/IL-23p40, interferon-γ, tumor necrosis factor-α, VEGF, and nerve growth factor-ß. Oclacitinib triggered reductions of some cytokines involved in allergic reactions, including TGF-ß1, IL-12/IL-23p40, and tumor necrosis factor-α; however, these reductions were less robust than the reductions triggered by OE and oleandrin and accompanied by increases in other cytokines involved in dermal inflammation, including IL-6, interferon-γ, and nerve growth factor-ß. In cultures of primary dermal fibroblasts, OE and oleandrin reduced the levels of IL-8 and monocyte chemoattractant protein-1, whereas oclacitinib had little or no effect. CONCLUSIONS: Oleander extract and oleandrin directly modulate immune responses under inflamed conditions. Moreover, OE and oleandrin appear to provide a more beneficial overall cytokine regulation than oclacitinib under inflamed culture conditions. CLINICAL RELEVANCE: These results suggest that OE and oleandrin are efficacious agents to treat canine atopic dermatitis. Future studies should evaluate the efficacy of these compounds in dogs affected by atopic dermatitis.

MrgprA3+ Primary Sensory Neurons Mediate Acute Allergic Itch Responses in Atopic Dermatitis Model Mice.

Itch is a prominent symptom of atopic dermatitis (AD). However, the underlying mechanism remains complex and has not yet been fully elucidated. Mas-related G protein-coupled receptor A3 (MrgprA3) has emerged attention as a marker of primary sensory neurons that specifically transmit itch signals; however, its involvement in AD-related itch has not been extensively explored. In this study, we developed an AD itch mouse model by repeatedly applying house dust mite (HDM) extract to barrier-impaired skin via a special diet. To clarify the role of MrgprA3+ neurons in itch behavior in our AD model, we adopted a toxin receptor-mediated cell knockout strategy using transgenic mice in which the diphtheria toxin receptor (DTR) gene was placed under the control of the Mrgpra3 promoter. When the HDM extract was repeatedly applied to the face and back skin of special diet-fed mice, the mice exhibited AD-like dry and eczematous skin lesions accompanied by three types of itch-related behaviors:1) spontaneous scratching, 2) acute scratching after antigen challenge, and 3) light touch-evoked scratching. Upon diphtheria toxin administration, substantial depletion of DTR+/MrgprA3+ neurons was observed in the dorsal root ganglion. Ablation of MrgprA3+ neurons suppressed acute itch responses after HDM application, whereas spontaneous and touch-evoked itch behaviors remained unaffected. Our findings unequivocally demonstrate that in our AD model, MrgprA3+ primary sensory neurons mediate acute allergic itch responses, whereas these neurons are not involved in spontaneous itch or alloknesis.

The neuroscience of itch in relation to transdiagnostic psychological approaches.

The experience of itch and its associated chronic conditions (i.e., atopic dermatitis) form a significant burden of disease. Knowledge of how the brain processes itch, that might occur uniquely for chronic itch populations, could be used to guide more effective psychotherapeutic interventions for these groups. To build the evidence base for such approaches, we conducted a series of coordinates-based fMRI analyses, to identify the shared neural mechanisms for itch across the published literature. Upon so doing, we identified a core "itch network" that spans the Basal Ganglia/Thalamus, Claustrum and Insula. Additionally, we found evidence that the Paracentral Lobule and Medial Frontal Gyrus, regions associated with cognitive control and response inhibition, deactivate during itch. Interestingly, a separate analysis for chronic itch populations identified significant recruitment of the Left Paracentral Lobule, potentially suggesting the recruitment of cognitive control mechanisms to resist the urge to scratch. We position these results in light of further integrative studies that could use neuroimaging alongside clinical studies, to explore how transdiagnostic psychological approaches-such as mindfulness and compassion training-might help to improve quality of life for individuals who experience chronic itch.

Baicalein ameliorates chronic itch in ACD mice by suppressing the spinal astrocytic STAT3-LCN2 cascade.

Chronic itch is a maladaptive and debilitating symptom in patients with allergic contact dermatitis (ACD), adversely affecting their quality of life. There is a lack of effective treatments for ACD-associated uncontrollable itch. In this study, we explored the antipruritic effects of baicalein (BE), a bioactive flavonoid extracted from the root of Scutellaria baicalensis Georgi, and the underlying mechanisms in alleviating chronic itch triggered by diphenylcyclopropenone (DCP) in a mouse model of ACD. The ACD mice were intraperitoneally injected with BE (5, 30, and 60 mg·kg-1·d-1) for 7 days during the DCP challenge phase. The results showed that DCP-treated mice exhibited severe spontaneous scratching behaviors that was reduced after BE injections in a dose-dependent manner accompanied by inhibition of spinal astrocyte activation. We observed that the spinal astrocytic STAT3-LCN2 cascade plays a crucial role in controlling the activation of astrocytes in chronic itch. Intrathecal injection of the STAT3 inhibitor AG490 or Lcn2 siRNA significantly reduced scratching behavior and astrocyte activation in ACD mice. Moreover, BE markedly attenuated the increased phosphorylation of STAT3 (p-STAT3) and LCN2 expression in the spinal cords of ACD mice and in lipopolysaccharide-stimulated primary spinal astrocytes. Altogether, BE relieved chronic itch by suppressing the spinal astrocytic STAT3-LCN2 cascade. These findings provide a potential avenue for the management of chronic itch. Schematic summary of the main findings illustrating that BE alleviates chronic itch through suppressing the spinal astrocytic STAT3-LCN2 cascade. Specifically, BE suppresses the expression of p-STAT3 to inhibit the reactive state of astrocytes in spinal dorsal horn, and then decreases the expression of astrocytic LCN2 to alleviate chronic itch in ACD mice.

Adjunctive Management of Itch in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin condition that can be difficult to treat due to a complex etiology and diverse clinical presentations. Itch is the most common symptom associated with AD with profound negative impact on quality of life. Thus, the adjunctive management of itch in patients with AD is needed to control and reduce disease burden. Supplemental treatment options are continuously emerging and undergoing testing in clinical trials. This article summarizes the latest data on topical and systemic adjunctive therapies for AD safety and efficacy in reducing itch.

She-Chuang-Si-Wu-Tang Alleviates Inflammation and Itching Symptoms in a Psoriasis Mouse Model by Regulating the Th17/IL-17 Axis via the STAT3/MAPK Pathways.

Purpose: Psoriasis is an immune-related disorder characterized by silver scales, epidermis thickness, and itching. She-Chuang-Si-Wu-Tang (SSWT), a traditional Chinese medicine decoction, has been used clinically for 400 years. Although it benefits psoriasis treatment, the mechanism of action is still unclear. This study explores SSWT's molecular mechanism in treating psoriasis through network pharmacology analysis and experiments. Methods: We identified relevant SSWT and psoriasis targets using network pharmacology and conducted SSWT quality control with high-performance liquid chromatography (HPLC). A mouse model of psoriasis was established using imiquimod (IMQ), with the drug administered continuously for seven days, spanning an eight-day period. During the experiment, we observed spontaneous scratching behaviors and assessed the Psoriasis Area and Severity Index (PASI) scores. At the conclusion of the experiment, we examined skin tissue pathology under an optical microscope and measured epidermal thickness. Additionally, we used enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to measure interleukin (IL)-23, IL-17A, IL-17F, and interferon (IFN)-γ levels in the mice's serum and their mRNA expression in the skin. Western blot analysis was conducted to assess protein levels related to signaling pathways. Results: Results indicate that SSWT may target IL-17 signaling pathways and T helper (Th) 17 cell differentiation, as predicted by network pharmacology. SSWT significantly improved the PASI and Baker scores, reduced epidermal thickness, and decreased spontaneous scratching in IMQ-induced mice. Additionally, SSWT treatment significantly lowered the concentrations of inflammatory factors in the serum and skin lesions, as well as mRNA expression levels, compared to the IMQ group. Furthermore, SSWT significantly inhibited the phosphorylation of both the signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) pathways. Conclusion: In summary, this study unveiled the potential anti-psoriatic mechanism of SSWT, offering new evidence for its clinical application.

Improvement Across Dimensions of Disease with Lebrikizumab Use in Atopic Dermatitis: Two Phase 3, Randomized, Double-Blind, Placebo-Controlled Monotherapy Trials (ADvocate1 and ADvocate2).

INTRODUCTION: Atopic dermatitis is a complex, chronic, inflammatory skin disease that requires long-term control of symptoms like itch and sleep loss and improvement in quality of life, in addition to reduction of clinical signs. Lebrikizumab is a selective interleukin-13 inhibitor approved in the European Union, United Kingdom, United Arab Emirates, Canada, and Japan for treatment of moderate-to-severe atopic dermatitis in adults and adolescents. Here, we assess the magnitude of changes across signs and symptoms of atopic dermatitis with lebrikizumab monotherapy over the 16-week induction period in two phase 3 studies, ADvocate1 and ADvocate2. METHODS: Eligible adults (aged ≥ 18 years) and adolescents (aged 12 to < 18 years and weighing ≥ 40 kg) with moderate-to-severe atopic dermatitis were randomized to receive either 250 mg of lebrikizumab or placebo subcutaneously every two weeks. Least squares mean percentage change from baseline through week 16 was compared between lebrikizumab and placebo using mixed model repeated measure analysis for the following endpoints: Eczema Area and Severity Index (EASI), Pruritus Numeric Rating Scale (NRS), Sleep-Loss Scale, Patient-Oriented Eczema Measure (POEM), and Dermatology Life Quality Index (DLQI). RESULTS: In both trials, significant (P < 0.05) improvements were observed for lebrikizumab treatment compared with placebo at each 2-week timepoint for EASI, Pruritus NRS, Sleep-Loss Scale, and POEM, and at each 4-week timepoint for DLQI, through week 16. Statistically significant (P < 0.001) improvements were observed at 16 weeks for lebrikizumab treatment versus placebo in ADvocate1/ADvocate2 for EASI (71.9%/75.0% vs. 35.6%/43.3%), Pruritus NRS (53.3%/46.3% vs. 21.4%/18.0%), Sleep-Loss Scale (57.7%/55.6% vs. 23.9%/25.5%), POEM (54.4%/45.8% vs. 18.8%/16.9%), and DLQI (64.2%/60.5% vs. 28.5%/32.2%). Patient photos show improvements in skin appearance when disease measures improve. CONCLUSIONS: Lebrikizumab monotherapy resulted in significant and fast improvements in multiple dimensions of disease (clinical signs, symptoms, and quality of life) over 16 weeks in patients with moderate-to-severe atopic dermatitis. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT04146363; NCT04178967.

TRPV4-ß-catenin axis is a novel therapeutic target for dry skin-induced chronic itch.

Dry skin induced chronic pruritus is an increasingly common and debilitating problem, especially in the elderly. Although keratinocytes play important roles in innate and adaptive immunity and keratinocyte proliferation is a key feature of dry skin induced chronic pruritus, the exact contribution of keratinocytes to the pathogenesis of dry skin induced chronic pruritus is poorly understood. In this study, we generated the acetone-ether-water induced dry skin model in mice and found that epidermal hyperplasia induced by this model is partly dependent on the ß-catenin signaling pathway. XAV939, an antagonist of ß-catenin signaling pathway, inhibited epidermal hyperplasia in dry skin model mice. Importantly, dry skin induced chronic pruritus also dramatically reduced in XAV939 treated mice. Moreover, acetone-ether-water treatment-induced epidermal hyperplasia and chronic itch were decreased in Trpv4-/- mice. In vitro, XAV939 inhibited hypo-osmotic stress induced proliferation of HaCaT cells, and hypo-osmotic stress induced proliferation of in HaCaT cells and primary cultured keratinocytes were also significantly reduced by blocking TRPV4 function. Finally, thymic stromal lymphopoietin release was examined both in vivo and in vitro, which was significantly inhibited by XAV939 treatment and Trpv4 deficiency, and anti-TSLP antibody treatment significantly decreased AEW-induced scratching behavior. Overall, our study revealed a unique ability of TRPV4 expressing keratinocytes in the skin, which critically mediated dry skin induced epidermal hyperplasia and chronic pruritus, thus provided novel insights into the development of therapies for chronic pruritus in the elderly.

PARVB deficiency alleviates cisplatin-induced tubular injury by inhibiting TAK1 signaling.

Cisplatin-induced renal tubular injury largely restricts the wide-spread usage of cisplatin in the treatment of malignancies. Identifying the key signaling pathways that regulate cisplatin-induced renal tubular injury is thus clinically important. PARVB, a focal adhesion protein, plays a crucial role in tumorigenesis. However, the function of PARVB in kidney disease is largely unknown. To investigate whether and how PARVB contributes to cisplatin-induced renal tubular injury, a mouse model (PARVB cKO) was generated in which PARVB gene was specifically deleted from proximal tubular epithelial cells using the Cre-LoxP system. In this study, we found depletion of PARVB in proximal tubular epithelial cells significantly attenuates cisplatin-induced renal tubular injury, including tubular cell death and inflammation. Mechanistically, PARVB associates with transforming growth factor-ß-activated kinase 1 (TAK1), a central regulator of cell survival and inflammation that is critically involved in mediating cisplatin-induced renal tubular injury. Depletion of PARVB promotes cisplatin-induced TAK1 degradation, inhibits TAK1 downstream signaling, and ultimately alleviates cisplatin-induced tubular cell damage. Restoration of PARVB or TAK1 in PARVB-deficient cells aggravates cisplatin-induced tubular cell injury. Finally, we demonstrated that PARVB regulates TAK1 protein expression through an E3 ligase ITCH-dependent pathway. PARVB prevents ITCH association with TAK1 to block its ubiquitination. Our study reveals that PARVB deficiency protects against cisplatin-induced tubular injury through regulation of TAK1 signaling and indicates targeting this pathway may provide a novel therapeutic strategy to alleviate cisplatin-induced kidney damage.

Cough and Itch: common mechanisms of irritation in the throat and skin.

Cough and itch are protective mechanisms in the body. Cough occurs as a reflex motor response to foreign body inhalation, while itch is a sensation that similarly evokes a scratch response to remove irritants from the skin. Both cough and itch can last for sustained periods, leading to debilitating chronic disorders that negatively impact quality of life. Understanding the parallels and differences between chronic cough and chronic itch may be paramount to developing novel therapeutic approaches. In this article, we identify connections in the mechanisms contributing to the complex cough and scratch reflexes and summarize potential shared therapeutic targets. An online search was performed using various search engines, including PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov from 1983 to 2024. Articles were assessed for quality, and those relevant to the objective were analyzed and summarized. The literature demonstrated similarities in the triggers, peripheral and central nervous system processing, feedback mechanisms, immunologic mediators, and receptors involved in the cough and itch responses, with the neuronal sensitization processes exhibiting the greatest parallels between cough and itch. Given the substantial impact on quality of life, novel therapies targeting similar neuroimmune pathways may apply to both itch and cough and provide new avenues for enhancing their management.

The effect of dupilumab on caregiver- and patient-reported outcomes in young children with moderate-to-severe atopic dermatitis: results from a placebo-controlled, phase 3 study.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) greatly impacts children/caregivers. OBJECTIVE: Evaluate the impact of treatment with dupilumab on caregiver- and patient-reported AD symptoms and quality of life (QoL) in young children. METHODS: In the LIBERTY AD PRESCHOOL (randomized, placebo-controlled) study, children aged 6 months to 5 years with moderate-to-severe AD received dupilumab or placebo plus low-potency topical corticosteroids for 16 weeks. This post-hoc analysis assessed the change from baseline to week 16 in caregiver-reported outcome measures of AD symptoms (e.g., itch and sleep) and QoL of patients and their caregivers/families. RESULTS: Dupilumab (n = 83) vs placebo (n = 79) provided significant improvements in caregiver-reported AD symptoms and QoL. Significant improvements were seen as early as week 4 and sustained through the end of the study. Additionally, dupilumab vs placebo provided rapid and significant improvement in QoL measures for the patients' caregivers/families. LIMITATIONS: Few patients aged <2 years; significance only reported for pre-specified endpoints; Infant's Dermatitis QoL Index severity strata adopted from Children's Dermatology Life Quality Index. CONCLUSION: Dupilumab improved AD symptoms and QoL in patients and their caregivers/families.

Integrative Treatment Approaches with Mind-Body Therapies in the Management of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex pathophysiology characterized by intense pruritus, often associated with psychological stress and atopic and non-atopic comorbidities that significantly reduce quality of life. The psychological aspects of AD and the interaction between the mind and body via the skin-brain axis have led to an interest in mind-body therapies (MBT). The aim of this article is, therefore, to reinforce the importance of psychodermatological care in AD. We performed a focused literature review on holistic practices or integrative MBT in AD, including education, cognitive behavioral therapy, habit reversal, meditation, mindfulness, hypnotherapy, eye movement desensitization and reprocessing, biofeedback, progressive muscle relaxation, autonomous sensory meridian response, music therapy, massage, and touch therapy. A multidisciplinary holistic approach with MBT, in addition to conventional pharmacologic antipruritic therapies, to break the itch-scratch cycle may improve AD outcomes and psychological well-being. Although there is a paucity of rigorously designed trials, evidence shows the potential benefits of an integrative approach on pruritus, pain, psychological stress, anxiety, depressive symptoms, and sleep quality. Relaxation and various behavioral interventions, such as habit reversal therapy for replacing harmful scratching with massaging with emollient 'plus', may reduce the urge to scratch, while education may improve adherence to conventional therapies.

Evaluating the Role of Vitamin D in Alleviating Chronic Pruritus: A Meta-Analysis.

Chronic pruritus is a distressing condition that significantly impacts patients' quality of life. Recent research has increasingly focused on the potential role of vitamin D, given its immunomodulatory properties, in managing this condition. This meta-analysis seeks to systematically assess the effectiveness of vitamin D supplementation in alleviating chronic pruritus across diverse clinical contexts. We conducted an extensive search through multiple databases, covering literature up to July 2024, to identify relevant randomized controlled trials (RCTs) that evaluated the effect of vitamin D on chronic pruritus. Eligible studies were those that provided data on changes in pruritus severity, as measured by standardized tools, before and after vitamin D treatment. The data were synthesized using a random-effects model to address variability among the studies. This meta-analysis is registered with PROSPERO (registration number: CRD42024579353). The findings indicate that vitamin D supplementation is associated with a significant reduction in pruritus severity, the skin lesion area, and levels of inflammatory cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP), compared to controls. These results suggest that vitamin D could be a promising therapeutic option for chronic pruritus, though further rigorous studies are required to validate these findings and to elucidate the mechanisms involved.

Mouse Models of Itch.

Murine models are vital preclinical and biological tools for studying itch. In this paper, we explore how these models have enhanced our understanding of the mechanisms underlying itch through both acute and chronic itch models. We provide detailed protocols and recommend experimental setups for specific models to guide researchers in conducting itch research. We distinguish between what constitutes a bona fide pruritogen versus a stimulus that causes pruritogen release, an acute itch model versus a chronic itch model, and how murine models can capture aspects of pruritus in human disease. Finally, we highlight how mouse models of itch have transformed our understanding and development of therapeutics for chronic pruritus in patients.

Severe Itch Related to Hard Workload Treated with Acupuncture: Unexpected Results - A Case report.

INTRODUCTION: The effects of work-related stress (WRS) on occupational health often lead to reduced well-being and long-term sick leave. Itching or pruritus, a skin inflammation with a rash that provokes the desire to scratch, often occurs during stressful periods in patients with a history of atopic dermatitis (AD). CASE PRESENTATION: This patient suffered from severe WRS together with long-term therapeutically resistant pruritus for 8 years, resulting in severe itching. He was provided with an intervention with acupuncture treatment (AT) to prevent a long-term sick leave. The results showed an unexpected reduction in itching, skin inflammation, and eczema. Additionally, the treatment enhanced the patient's emotional and cognitive well-being and eliminated the need for sick leave. CONCLUSION: Acupuncture can be an effective complementary treatment for severe itching related to WRS, in addition to standard medical treatments.

Cell Type-Specific Modulation of Acute Itch Processing in the Anterior Cingulate Cortex.

Despite remarkable progress in understanding the fundamental bases of itching, its cortical mechanisms remain poorly understood. Herein, the causal contributions of defined anterior cingulate cortex (ACC) neuronal populations to acute itch modulation in mice are established. Using cell type-specific manipulations, the opposing functions of ACC glutamatergic and GABAergic neurons in regulating acute itching are demonstrated. Photometry studies indicated that ACC glutamatergic neurons are activated during scratching induced by both histamine and chloroquine, whereas the activation pattern of GABAergic neurons is complicated by GABAergic subpopulations and acute itch modalities. By combining cell type- and projection-specific techniques, a thalamocortical circuit is further identified from the mediodorsal thalamus driving the itch-scratching cycle related to histaminergic and non-histaminergic itching, which is contingent on the activation of postsynaptic parvalbumin-expressing neurons in the ACC. These findings reveal a cellular and circuit signature of ACC neurons orchestrating behavioral responses to itching and may provide insights into therapies for itch-related diseases.

Pruritus in Lichen Planopilaris and Frontal Fibrosing Alopecia-Clinical Characteristics and Dermoscopic Correlations.

Background: Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are the most common causes of lymphocytic scarring alopecia. Itching of the scalp is a common accompanying symptom. The aim of the study was the clinical assessment of pruritus and its correlation with dermoscopic features. Methods: Sixty-one patients with scarring alopecia were analyzed (LPP = 16; FFA = 33; coexisting LPP-FFA = 12). Each patient underwent a trichoscopic examination. Itch severity and characteristics were assessed using a Visual Analogue Scale (VAS), 4-item Itch Questionnaire and 12-item Descriptive Pruritus Assessment Questionnaire. Results: Itching of the scalp occurred in 73.8% of the patients (mean maximal VAS 5.3 ± 3.1 points). Pruritus was most frequently accompanied by tingling (19.7%) or burning (14.8%) sensations. The following factors most frequently increased the severity of pruritus: sweating, heat, stress and hot water. On the other hand, cold water and cold air often relieved symptoms. There was a significant relationship between itch and perifollicular scaling (p = 0.011), hair diameter diversity (p = 0.008) and white halo (p = 0.016). Conclusions: Pruritus was the main subjective complaint reported by patients suffering from LPP and FFA. A better understanding of pruritic features may help in the selection of an effective therapeutic strategy.