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Rosacea is a frequent chronic inflammatory skin disease of unknown etiology. Because early rosacea reveals all characteristics of neurogenic inflammation, a central role of sensory nerves in its pathophysiology has been discussed. Neuroinflammatory mediators and their receptors involved in rosacea are poorly defined. Good candidates may be transient receptor potential (TRP) ion channels of vanilloid type (TRPV), which can be activated by many trigger factors of rosacea. Interestingly, TRPV2, TRPV3, and TRPV4 are expressed by both neuronal and non-neuronal cells. Here, we analyzed the expression and distribution of TRPV receptors in the various subtypes of rosacea on non-neuronal cells using immunohistochemistry, morphometry, double immunoflourescence, and quantitative real-time PCR (qRT-PCR) as compared with healthy skin and lupus erythematosus. Our results show that dermal immunolabeling of TRPV2 and TRPV3 and gene expression of TRPV1 is significantly increased in erythematotelangiectatic rosacea (ETR). Papulopustular rosacea (PPR) displayed an enhanced immunoreactivity for TRPV2, TRPV4, and also of TRPV2 gene expression. In phymatous rosacea (PhR)-affected skin, dermal immunostaining of TRPV3 and TRPV4 and gene expression of TRPV1 and TRPV3 was enhanced, whereas epidermal TRPV2 staining was decreased. Thus, dysregulation of TRPV channels also expressed by non-neuronal cells may be critically involved in the initiation and/or development of rosacea. TRP ion channels may be targets for the treatment of rosacea.

In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.

The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo, precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR-Ras signaling pathways in keratinocyte-derived malignancies. In vitro, exogenous stimulation of the EGFR-Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses.

Proteinase-activated receptor-2 (PAR2) belongs to a new G protein-coupled receptor subfamily that is activated by various serine proteases. Recent knowledge indicates that PAR2 is involved in cutaneous inflammation and immune response. PAR2 is highly expressed by human keratinocytes (KTC). The underlying mechanisms of PAR2-mediated KTC function and cutaneous immune response are, however, still incomplete. Therefore, we investigated the activation of important signaling cascades in primary human KTC after PAR2-stimulation using specific agonists. Moreover, we compared PAR2-immunoreactivity in the epidermis of inflammatory dermatoses and normal human skin. Electrophoretic mobility shift assays and morphological transduction studies revealed PAR2-induced activation and translocation of nuclear factor kappa B (NF-κB) in primary human KTC with a maximum after 1 h. Supershift analysis demonstrated acivation of the p50/p65 heterodimer complex. PAR2 agonists also induced upregulation of intercellular adhesion molecule-1 (ICAM-1) RNA, as shown by RT-PCR. Use of NF-κB inhibitors prevented upregulation of the cell adhesion molecule ICAM-1 in KTC indicating a direct role of NF-κB in PAR2-mediated upregulation of ICAM-1. Fluorescence-activated cell sorter analysis confirmed PAR2-induced and NF-κB-mediated upregulation of ICAM-1 protein after 13 h. Moreover, increased expression of PAR2 was detected in KTC of patients with atopic dermatitis suggesting a role of PAR2 in human skin inflammation. In conclusion, PAR2 induces upregulation of cell adhesion molecules such as ICAM-1 in primary human KTC via NF-κB activation, and is upregulated in KTC during cutaneous inflammation. Thus, PAR2 may play an important regulatory role of human KTC during inflammation and immune response.

The proteinase-activated receptor PAR2 has been demonstrated to modulate tumor growth, invasion and metastasis in various tissues. However, the role of PAR2 in cutaneous cancerogenesis is still unknown. Here we could show a protective role of PAR2 in the development of epidermal skin tumors: we established a mouse skin tumor model using chemically induced carcinogenesis. Tumors started to appear after eight weeks. After 13 weeks, PAR2-deficient mice showed a significantly increased number of skin tumors (14 per animal on the average) in contrast to the wild type (eight tumors per mouse). Analysis of possible signal transduction pathways activated upon PAR2 stimulation in HaCaT keratinocytes showed an involvement of extracellular signal-regulated kinase 1/2 and profound epidermal growth factor receptor transactivation, leading to secretion of the tumor-suppressing factor transforming growth factor-β1. Thus, our results provide early experimental evidence for a tumor-protective role of PAR2.

Rosacea is a common skin disease with a high impact on quality of life. Characterized by erythema, edema, burning pain, immune infiltration, and facial skin fibrosis, rosacea has all the characteristics of neurogenic inflammation, a condition induced by sensory nerves via antidromically released neuromediators. To investigate the hypothesis of a central role of neural interactions in the pathophysiology, we analyzed molecular and morphological characteristics in the different subtypes of rosacea by immunohistochemistry, double immunofluorescence, morphometry, real-time PCR, and gene array analysis, and compared the findings with those for lupus erythematosus or healthy skin. Our results showed significantly dilated blood and lymphatic vessels. Signs of angiogenesis were only evident in phymatous rosacea. The number of mast cells and fibroblasts was increased in rosacea, already in subtypes in which fibrosis is not clinically apparent, indicating early activation. Sensory nerves were closely associated with blood vessels and mast cells, and were increased in erythematous rosacea. Gene array studies and qRT-PCR confirmed upregulation of genes involved in vasoregulation and neurogenic inflammation. Thus, dysregulation of mediators and receptors implicated in neurovascular and neuroimmune communication may be crucial at early stages of rosacea. Drugs that function on neurovascular and/or neuroimmune communication may be beneficial for the treatment of rosacea.

Background The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment. Methods The effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo. Results Tumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system. Conclusion We propose that the chemokine axis CCL20–CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy.

Since the beginning of the coronavirus pandemic and the associated lockdown measures, the number of children treated in this children's hospital for eating disorders and in particular anorexia nervosa has significantly increased.An increased focus on the control of body weight with restrictive eating habits or otherwise induced weight loss (sport) can compensate for fears of loss of control. Thinking and behavioral patterns which are typical for anorexia can be assessed as dysfunctional coping strategies of the corona pandemic in order to regain control (in the sense of a substitute structure) but also as a means of coping better with feelings of depression and anxiety.

Seit Beginn der Coronapandemie und den damit einhergehenden Lockdownmaßnahmen steigen die Behandlungszahlen für Kinder und Jugendliche mit Essstörungen und insbesondere mit Anorexia nervosa in der Klinik für Kinder und Jugendliche, KJF Klinik St. Elisabeth in Neuburg/Donau deutlich. Eine verstärkte Fokussierung auf die Kontrolle des Körpergewichts durch restriktives Essverhalten oder anderweitig herbeigeführte Gewichtsabnahme (Sport) kann Ängste vor Kontrollverlust kompensieren. Anorexietypische Denk- und Verhaltensmuster können als dysfunktionale Bewältigungsstrategien (Coping-Strategien), ausgelöst durch Lockdownmaßnahmen im Rahmen der Coronapandemie, gewertet werden, um Kontrollerleben (im Sinne einer Ersatzstruktur) wiederzuerlangen, aber auch um Depressions- und Angstgefühle besser bewältigen zu können.

A giant umbilical cord is a rare finding in mature newborns and originates from different developmental etiologies. We report on a case of a mature female newborn presenting a 50 × 8–cm giant umbilical cord without further malformations. Antenatal sonographic findings of a diffuse giant umbilical cord, elevated creatinine levels of 1.3 mg/dL in umbilical cord edema, gross and histopathological findings of allantoic remnants, and umbilical urinary discharge lead to the diagnosis of a patent urachus with retrograde micturition into the umbilical cord. Postnatal surgical repair was required. In antenatal sonography, cystic and diffuse changes should be considered in the differential diagnosis of a giant umbilical cord. In cases of diffuse enlargement, elevated umbilical creatinine can support the diagnosis of a patent urachus with open leakage into the Wharton's jelly. Appropriate surgical management is required.