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Epithelial/immune interactions are characterized by the different properties of the various epithelial tissues, the mediators involved, and the varying immune cells that initiate, sustain, or abrogate allergic diseases on the surface. The intestinal mucosa, respiratory mucosa, and regular skin feature structural differences according to their primary function and surroundings. In the context of these specialized functions, the active role of the epithelium in shaping immune responses is increasingly recognizable. Crosstalk between epithelial and immune cells plays an important role in maintaining homeostatic conditions. While cells of the myeloid cell lineage, mainly macrophages, are the dominating immune cell population in the skin and the respiratory tract, lymphocytes comprise most intraepithelial immune cells in the intestine under healthy conditions. Common to all surface epithelia is the fact that innate immune cells represent the first line of immunosurveillance that either directly defeats invading pathogens or initiates and coordinates more effective successive immune responses involving adaptive immune cells and effector cells. Pharmacological approaches for the treatment of allergic and chronic inflammatory diseases involving epithelial barriers target immunological mediators downstream of the epithelium (such as IL‐4, IL‐5, IL‐13, and IgE). The next generation of therapeutics involves upstream events of the inflammatory cascade, such as epithelial‐derived alarmins and related mediators. [ABSTRACT FROM AUTHOR]

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Summary: Background: Visible blue light (wavelength 400–495 nm) is a promising new treatment option for both psoriasis and atopic dermatitis (AD). Whilst previous clinical trials featured various devices and blue light at a variety of wavelengths, none of these interventions were challenged in objective clinical criteria. Patients and Methods: Eighty‐seven patients diagnosed with AD were enrolled in AD‐Blue, an international, prospective, double‐blinded, three‐armed (415 nm vs. 450 nm vs. sham control), randomized trial designed to investigate the safety and efficacy of prototype full‐body blue light devices. Results: Full‐body irradiation with 450 nm blue light but not 415 nm had a significant impact on itch (Itch‐VAS, –1.6 ± 2.3; p = 0.023 vs. sham irradiation). PO‐SCORAD values also decreased significantly in response to irradiation at 415 nm (–11.5 ± 18.4; p = 0.028 vs. sham irradiation). None of the other outcome measures (EASI, SCORAD, IGA, DLQI) changed significantly. No safety signals were observed. Evaluation of skin transcriptomes, cytokine levels in serum, and ELISpots from peripheral blood mononuclear cells isolated from a subset of patients revealed moderate decreases in IL‐31 in response to irradiation with blue light. Conclusions: Despite its favorable safety profile and moderate reductions in itch and IL‐31 levels, full‐body blue light irradiation did not lead to an amelioration of any of the objective measures of AD. [ABSTRACT FROM AUTHOR]

Summary: Background: The association of atopic dermatitis (AD) and allergic contact dermatitis has been a matter of considerable uncertainty. Study results range from lack of any association to increased sensitization for multiple allergens, but fail to identify consistent allergen associations. Objective: We studied a large patch test cohort of patients stratified by their atopic skin diathesis using the Erlangen Atopy Score (EAS), independent of active skin disease. Methods: Retrospective multi‐center data analysis from five departments of dermatology in Germany with 4,509 patients. Patients were grouped as "no atopic skin diathesis" (n = 2,165) and "atopic skin diathesis" (n = 1,743), according to EAS. Results: Significantly more individuals with atopic skin diathesis showed at least one positive patch test reaction to the baseline series compared to individuals without atopic skin diathesis (49.1 % vs. 38.3 %). In logistic regression analyses, atopic skin diathesis was associated with a significantly higher risk of sensitization to methylchloroisothiazolinone/methylisothiazolinone (OR 2.383) and methylisothiazolinone (OR 1.891), thiuram mix (OR 1.614), as well as nickel (OR 1.530), cobalt (OR 1.683), and chromium (OR 2.089). Conclusions: Atopic skin diathesis proved to be the most important intrinsic risk factor for contact sensitization to few, specific allergens. Past or present AD was a less relevant variable. [ABSTRACT FROM AUTHOR]

Background: Activation of protease-activated receptor-2 (PAR2) has been implicated in inflammation, pruritus, and skin barrier regulation, all characteristics of atopic dermatitis (AD), as well as Netherton syndrome which has similar characteristics. However, understanding the precise role of PAR2 on neuro-immune communication in AD has been hampered by the lack of appropriate animal models. Methods: We used a recently established mouse model with epidermal overexpression of PAR2 (PAR2OE) and littermate WT mice to study the impact of increased PAR2 expression in epidermal cells on spontaneous and house dust mite (HDM)-induced skin inflammation, itch, and barrier dysfunction in AD, in vivo and ex vivo. Results: PAR2OE newborns displayed no overt abnormalities, but spontaneously developed dry skin, severe pruritus, and eczema. Dermatological, neurophysiological, and immunological analyses revealed the hallmarks of AD-like skin disease. Skin barrier defects were observed before onset of skin lesions. Application of HDM onto PAR2OE mice triggered pruritus and the skin phenotype. PAR2OE mice displayed an increased density of nerve fibers, increased nerve growth factor and endothelin-1 expression levels, alloknesis, enhanced scratching (hyperknesis), and responses of dorsal root ganglion cells to non-histaminergic pruritogens. Conclusion: PAR2 in keratinocytes, activated by exogenous and endogenous proteases, is sufficient to drive barrier dysfunction, inflammation, and pruritus and sensitize skin to the effects of HDM in a mouse model that mimics human AD. PAR2 signaling in keratinocytes appears to be sufficient to drive several levels of neuro-epidermal communication, another feature of human AD. [ABSTRACT FROM AUTHOR]

Background: Filaggrin (Flg) and hornerin (Hrnr) share similar structural and functional features. Both proteins have been implicated as essential proteins for skin barrier maintenance. Loss‐of‐function mutations of these genes constitute a risk factor for atopic dermatitis and eczema‐related asthma. Furthermore, both FLG and HRNR protein levels are downregulated in patients with atopic dermatitis. Thus, mice deficient for Flg and Hrnr provide a novel model to study skin barrier impairment and the susceptibility for cutaneous inflammation. Methods: By using appropriate targeting vectors and breeding strategies, we established a homozygous FlgHrnr double‐deficient (FlgHrnr−/−) mouse model lacking both genes including the intergenomic sequence. Results: Neonates appeared normal, but developed a transient scaly phenotype with overall flaky appearance, but no overt skin phenotype in adulthood, thereby reflecting a subclinical barrier defect seen in humans. Structurally, FlgHrnr−/− mice displayed a markedly reduced granular layer and a condensed cornified layer. Functionally, FlgHrnr−/− mice showed permeability abnormalities and metabolic aberrations regarding the production of natural moisturizing factors (NMFs) in the stratum corneum. Surprisingly, although the immune system revealed no aberrations under steady‐state conditions, FlgHrnr−/− mice are predisposed to mount an allergic contact dermatitis, especially at hapten threshold levels eliciting allergic reactions. Conclusions: Together, our FlgHrnr−/− mouse model nicely reflects the epicutaneous sensitization susceptibilities and inflammatory reactions to environmental insults in humans with impaired skin barrier functions. [ABSTRACT FROM AUTHOR]

The article presents the case study of 31-year-old non-atopic toolmaker being exposed to a concentrated solution with an oligomeric reaction product, with diphenylmethane and tripropyleneglycol. It states that the patient wore protective gloves and goggles, his right forearm and face that were contaminated. It focuses application of topical corticosteroids in the affected are.

Background T H 2 cell–released IL-31 is a critical mediator in patients with atopic dermatitis (AD), a prevalent and debilitating chronic skin disorder. Brain-derived natriuretic peptide (BNP) has been described as a central itch mediator. The importance of BNP in peripheral (skin-derived) itch and its functional link to IL-31 within the neuroimmune axis of the skin is unknown. Objective We sought to investigate the function of BNP in the peripheral sensory system and skin in IL-31–induced itch and neuroepidermal communication in patients with AD. Methods Ca 2+ imaging, immunohistochemistry, quantitative real-time PCR, RNA sequencing, knockdown, cytokine/phosphokinase arrays, enzyme immune assay, and pharmacologic inhibition were performed to examine the cellular basis of the IL-31–stimulated, BNP-related itch signaling in dorsal root ganglionic neurons (DRGs) and skin cells, transgenic AD-like mouse models, and human skin of patients with AD and healthy subjects. Results In human DRGs we confirmed expression and co-occurrence of oncostatin M receptor β subunit and IL-31 receptor A in a small subset of the neuronal population. Furthermore, IL-31 activated approximately 50% of endothelin-1–responsive neurons, and half of the latter also responded to histamine. In murine DRGs IL-31 upregulated Nppb and induced soluble N-ethylmaleimide–sensitive factor activating protein receptor–dependent BNP release. In Grhl3PAR2 /+ mice house dust mite–induced severe AD-like dermatitis was associated with Nppb upregulation. Lesional IL-31 transgenic mice also exhibited increased Nppb transcripts in DRGs and the skin; accordingly, skin BNP receptor levels were increased. Importantly, expression of BNP and its receptor were increased in the skin of patients with AD. In human skin cells BNP stimulated a proinflammatory and itch-promoting phenotype. Conclusion For the first time, our findings show that BNP is implicated in AD and that IL-31 regulates BNP in both DRGs and the skin. IL-31 enhances BNP release and synthesis and orchestrates cytokine and chemokine release from skin cells, thereby coordinating the signaling pathways involved in itch. Inhibiting peripheral BNP function might be a novel therapeutic strategy for AD and pruritic conditions. [ABSTRACT FROM AUTHOR]

Background Despite recent insights into the pathophysiology of acute and chronic itch, chronic itch remains an often intractable condition. Among major contributors to chronic itch is dysfunction of spinal cord gamma aminobutyric acidergic (GABAergic) inhibitory controls. Objectives We sought to test the hypothesis that selective GABA agonists as well as cell transplant-derived GABA are antipruritic against acute itch and in a transgenic mouse model of atopic dermatitis produced by overexpression of the T H 2 cell-associated cytokine, IL-31 (IL-31Tg mice). Methods We injected wild-type and IL-31Tg mice with combinations of GABA-A (muscimol) or GABA-B (baclofen) receptor agonists 15 to 20 minutes prior to injection of various pruritogens (histamine, chloroquine, or endothelin-1) and recorded spontaneous scratching before and after drug administration. We also tested the antipruritic properties of intraspinal transplantation of precursors of GABAergic interneurons in the IL-31Tg mice. Results Systemic muscimol or baclofen are antipruritic against both histamine-dependent and -independent pruritogens, but the therapeutic window using either ligand alone was very small. In contrast, combined subthreshold doses of baclofen and muscimol produced a significant synergistic antipruritic effect, with no sedation. Finally, transplant-mediated long-term enhancement of GABAergic signaling not only reduced spontaneous scratching in the IL-31Tg mice but also dramatically resolved the associated skin lesions. Conclusions Although additional research is clearly needed, existing approved GABA agonists should be considered in the management of chronic itch, notably atopic dermatitis. [ABSTRACT FROM AUTHOR]

Background: Although the cytokine IL-31 has been implicated in inflammatory and lymphoma-associated itch, the cellular basis for its pruritic action is yet unclear. Objective: We sought to determine whether immune cell–derived IL-31 directly stimulates sensory neurons and to identify the molecular basis of IL-31–induced itch. Methods: We used immunohistochemistry and quantitative real-time PCR to determine IL-31 expression levels in mice and human subjects. Immunohistochemistry, immunofluorescence, quantitative real-time PCR, in vivo pharmacology, Western blotting, single-cell calcium imaging, and electrophysiology were used to examine the distribution, functionality, and cellular basis of the neuronal IL-31 receptor α in mice and human subjects. Results: Among all immune and resident skin cells examined, IL-31 was predominantly produced by TH2 and, to a significantly lesser extent, mature dendritic cells. Cutaneous and intrathecal injections of IL-31 evoked intense itch, and its concentrations increased significantly in murine atopy-like dermatitis skin. Both human and mouse dorsal root ganglia neurons express IL-31RA, largely in neurons that coexpress transient receptor potential cation channel vanilloid subtype 1 (TRPV1). IL-31–induced itch was significantly reduced in TRPV1-deficient and transient receptor channel potential cation channel ankyrin subtype 1 (TRPA1)–deficient mice but not in c-kit or proteinase-activated receptor 2 mice. In cultured primary sensory neurons IL-31 triggered Ca2+ release and extracellular signal-regulated kinase 1/2 phosphorylation, inhibition of which blocked IL-31 signaling in vitro and reduced IL-31–induced scratching in vivo. Conclusion: IL-31RA is a functional receptor expressed by a small subpopulation of IL-31RA+/TRPV1+/TRPA1+ neurons and is a critical neuroimmune link between TH2 cells and sensory nerves for the generation of T cell–mediated itch. Thus targeting neuronal IL-31RA might be effective in the management of TH2-mediated itch, including atopic dermatitis and cutaneous T-cell lymphoma. [Copyright &y& Elsevier]

Chronic itch is a complex sensation of the skin frequently associated with skin diseases, such as atopic dermatitis (AD) and psoriasis. Although Serpin E1 is implicated in chronic itch, its receptor and signaling pathways involved in itch are not known. In this study, the clinical relevance of a putative Serpin E1 receptor PLAUR to chronic itch, and the neuro‐cutaneous Serpin E1‐PLAUR signaling are explored. We found that PLAUR is overexpressed in skin specimens of human lesional AD and lesional psoriasis, and sensory neurons innervating MC903‐induced AD‐like murine skin. Murine PLAUR+ sensory neurons responded to Serpin E1, resulting in enrichment of numerous itch‐ and inflammation‐related genes and their protein release. PLAUR resides in TLR2+ neurons and Serpin E1 stimulus led to transcriptional upregulation of TLR2 and its co‐signaling proteins. Agonists of TLR2 propagated itch‐related gene transcription including BNP, OSM, and PAR2. OSM induced acute itch in mice and promoted G‐CSF and IL‐8 release from human keratinocytes. Serpin E1 inhibitor reduced MC903‐induced itch, epidermal hyperplasia, immunocyte infiltration, and resulted in lower transcription/expression levels of Serpin E1 and OSM. Taken together, the PLAUR‐TLR2‐OSM signaling promotes skin‐nerve communication, cutaneous inflammation, and itch, all feeding into an aggravation of AD and exaggerated itch circuits. [ABSTRACT FROM AUTHOR]

• AD disease driven-upregulation of IL-13Rα2 in keratinocytes and peripheral neurons contributes to cutaneous inflammation and itch sensation. • TLR2 innate immune modulates transcription and activation of peripheral IL-13Rα2 to promote itch signaling and neurogenic inflammation. • IL-13Rα2 regulates itch-related receptor and mediators, including EDNRA, CCL17, CCL20, CCL26, CXCL6, SERPIN family and chemerin. • IL-13Rα2 signaling is a suitable target for refractory atopic dermatitis associated with skin infection. The clinical significance and regulators of IL-13Rα2 in itch and atopic dermatitis (AD) remain unclear. To identify disease-driven regulatory circuits of IL-13Rα2, transcriptomic/pathological analysis was performed in skin from patients with AD, psoriasis, healthy subjects, and murine AD model. Functionality was investigated in sensory neurons, keratinocytes and animal model, by using knockdown (KD), calcium imaging, RNA-seq, cytokine arrays, pharmacological assays, and behavioural investigations. In our study, an upregulated IL-13Rα2 expression was revealed in skin of AD patients, but not psoriasis, in a disease activity-dependent manner. In cultured human keratinocytes, IL-13 increased IL-13Rα2 transcription levels, and this were downregulated by IL-13Rα1KD. IL-13Rα2KD reduced transcription levels of EDNRA, CCL20, CCL26. In contrast, sensory neuron-derived IL-13Rα2 was upregulated by TLR2 heterodimer agonists, Pam3CSK4 and FSL-1. In a mouse cheek model, pre-administration of Pam3CSK4 and FSL-1 enhanced IL-13-elicited scratching behaviour. Consistently, in cultured sensory neurons Pam3CSK4 enhanced IL-13-elicted calcium transients, increased number of responders, and orchestrated chemerin, CCL17 and CCL22 release. These release was inhibited by IL-13Rα2KD. Collectively, IL-13 regulates keratinocyte-derived IL-13Rα2 and TLR2 to modulate neuronal IL-13Rα2, thereby promoting neurogenic inflammation and exacerbating AD and itch. Thus, the cutaneous IL-13-IL-13Rα2 and neuronal TLR2-IL-13Rα2 pathway represent important targets to treat AD and itch. [ABSTRACT FROM AUTHOR]