Neuropeptides: role in inflammatory skin diseases

The cutaneous nervous system recently has been demonstrated to interact with multiple target cells in the skin and to mediate actions important in inflammatory conditions. Neuropeptides released by cutaneous neurons such as substance P (SP), vasointenstinal peptide (VIP), calcitonine gene regulated peptide (CGRP), proopiomelancortin (POMC) peptides and others modulate the function of immunocompetent and inflammatory cells as well as epithelial and endothelial cells. They have been found to function as mediators of cell proliferation, cytokine and growth factor production as well as adhesion molecule and cell surface receptor expression. In addition many cells including keratinocytes, fibroblasts, endothelial cells and inflammatory cells have been shown to release several neuropeptides and they express their corresponding receptors. These findings indicate that neuropeptides participate in the complex network of mediators that regulate cutaneous inflammation, hyperproliferation and wound healing.     

Update on the role of plasmacytoid dendritic cells in inflammatory/autoimmune skin diseases

Plasmacytoid dendritic cells (pDCs) represent a specialized dendritic cell population that exhibit plasma cell morphology, express CD4, CD123, blood‐derived dendritic cell antigen‐2 (BDCA‐2) and Toll‐like receptor (TLR)7 and TLR9 within endosomal compartments. When activated, pDCs are capable of producing large quantities of type I IFNs (mainly IFN‐α/β), which provide antiviral resistance and link the innate and adaptive immunity. While generally lacking from normal skin, pDCs infiltrate the skin and appear to be involved in the pathogenesis of several inflammatory, infectious (especially viral) and neoplastic entities. In recent years, pDC role in inflammatory/autoimmune skin conditions has been extensively studied. Unlike type I IFN‐mediated protective immunity that pDCs provide at the level of the skin by regulated sensing of microbial or self‐nucleic acids upon skin damage, excessive sensing may elicit IFN‐driven inflammatory/autoimmune diseases. In this review, focus will be on the role of pDCs in cutaneous inflammatory/autoimmune dermatoses.     

The role of ceramides in skin homeostasis and inflammatory skin diseases

Ceramides, members of sphingolipid family, are not only the building blocks of epidermal barrier structure, but also bioactive metabolites involved in epidermal self-renewal and immune regulation. Hence, abnormal ceramide expression profile is recognized to defect extracellular lipid organization, disturb epidermal self-renewal, exacerbate skin immune response and actively participate in progression of several inflammatory dermatoses, exemplifying by psoriasis and atopic dermatitis. Here, we discuss recent advances in understanding skin ceramides and their regulatory roles in skin homeostasis and pathogenic roles of altered ceramide metabolism in inflammatory skin diseases. These insights provide new opportunities for therapeutic intervention in inflammatory dermatoses.     

The many faces of interleukin‐17 in inflammatory skin diseases

Interleukin (IL)‐17 is an emerging target for inflammatory skin disorders. Given the remarkable success of its therapeutic inhibition in psoriasis, the pathogenic role of this cytokine is being explored in other immune‐mediated diseases. Interestingly, IL‐17 is linked to particular skin conditions where its activation coincides with disease flares. The leading hypothesis for its contribution to proinflammatory signalling cascades is driving inflammasome activation. However, IL‐17 stimulation also releases a range of noninflammasome‐related cytokines from human skin. Furthermore, a role in cytotoxic responses and an important interplay with the microbiome is hypothesized. While treatment failure would be surprising in neutrophilic dermatoses, the picture might be more complex in lymphocyte‐mediated conditions. Nonetheless, increasing insights into the pathogenesis suggest that beneficial responses are also probable in the latter conditions. Study of this pathway in the skin reveals some intriguing aspects of the IL‐17‐related immunological network.     

白介素17与自身免疫性皮肤病

白介素17是由Th17细胞分泌的炎症细胞因子,在机体炎症及免疫性疾病中发挥重要作用.皮肤自身免疫性疾病的发病机制尚不清楚.IL-17的炎性和免疫性双重特征,有望在皮肤自身免疫性疾病的研究中取得突破.进一步研究IL-17在皮肤自身免疫性疾病中的作用,探讨其发病机制,可有效寻找新的药物作用靶点和新的治疗方法.     

TRP通道在炎症性皮肤病中的作用

瞬时受体电位(TRP)通道是一类非特异性阳离子通道蛋白家族,在皮肤感觉神经元和非神经元细胞中广泛表达,能被多种刺激激活,参与炎症性皮肤病的发生发展。本文重点对TRP通道的不同亚型在玫瑰痤疮、特应性皮炎、银屑病、接触性皮炎等炎症性皮肤病中的作用进行综述,提示TRP通道有望成为炎症性皮肤病的潜在治疗靶点。     

Exosomes in chronic inflammatory skin diseases and skin tumors

Exosomes are membrane vesicles of endocytic origin that can mediate communication between cells and the transport of cellular components such as microRNAs, mRNAs, proteins and DNA. Recently, exosomes have been under investigation for their significant roles in both healthy physiology and disease states. Herein, we review the role of exosomes in chronic inflammatory skin diseases and skin tumors, especially focusing on systemic lupus erythematosus, psoriasis, atopic dermatitis, bullous pemphigoid and melanoma. Moreover, we emphasize the involvement of changes in exosome cargo in the regulation of these diseases.     

Regulatory T cells in autoimmune skin diseases

CD4⁺Foxp3⁺ regulatory T cells (Tregs) are suppressors of immune activation and play a crucial role in the maintenance of peripheral tolerance. Mutations of Foxp3 result in fatal autoimmunity in multiple organs, including the skin, in both humans and mice. Many studies have demonstrated the altered frequency and functions of Tregs, changes in cytokine and chemokine levels related to Tregs and the differences in genetic background regarding Tregs in autoimmune skin disorders. Recent studies have extended our knowledge of certain properties of Tregs, especially skin‐resident Tregs. In addition, some novel therapies have been performed by modulating the number and the function of Tregs. This review focuses on the role of Tregs in some autoimmune skin disorders, including alopecia areata, vitiligo, pemphigoid and pemphigus, and systemic sclerosis, and discusses questions that remain to be addressed.     

Th17细胞与皮肤病

Th17细胞亚群是近年来发现的一类CD4+T细胞亚群,产生白介素-17、6、22和肿瘤坏死因子-α而不产生干扰素-γ和白介素-4,可介导慢性炎症反应、自身免疫性疾病、肿瘤和移植排斥等,在机体免疫调节、免疫病理和宿主防御反应中发挥重要作用.白介素-17是一种强大的促炎因子,可发挥与Toll样受体激动剂相似的作用激活固有免疫,同时也是炎症反应的微调因子,能与多种细胞因子产生协同作用,放大炎性效应,促进许多自身免疫性疾病的发生和发展.研究表明,系统性红斑狼疮、银屑病、蕈样肉芽肿及特应性皮炎等患者相关血清因子水平异常,提示Th17细胞与T细胞介导的皮肤慢性炎症及自身免疫性疾病有关.     

内源性大麻素系统与炎症性皮肤病

内源性大麻素系统包括内源性大麻素受体和内源性大麻素以及一系列参与内源性大麻素系统生物合成和代谢的酶类以及膜转运受体.近年来,在角质形成细胞、皮肤成纤维细胞、皮脂腺细胞等多种皮肤细胞中发现了具有生物学效应的内源性大麻素系统.越来越多的研究发现,内源性大麻素系统参与正常皮肤生理生化活动和炎症反应,并在多种炎症性皮肤病中起作用.目前内源性大麻素系统的临床应用尚不成熟,但内源性大麻素系统的研究为临床炎症性皮肤病的治疗提供了新视角和新策略.     

Bacterial superantigens and inflammatory skin diseases

Bacteria seem to play an important role in the induction and maintenance of inflammatory skin diseases such as psoriasis and atopic dermatitis. Toxins from bacteria including Streptococcus and Staphylococcus aureus, have been shown to function as a new type of allergen termed 'superantigen'. Superantigens bypass the normal control of T-cell activation and activate all T-cell clones bearing certain types of variable chain on the T-cell receptor: this leads to vigorous T-cell activation and cytokine release. These bacterial superantigens may be involved in induction and aggravation of inflammatory skin diseases. Guttate psoriasis is often preceded by a streptococcal throat infection and T cells specific for streptococcal superantigens have been identified in the skin of patients. The skin of patients with atopic dermatitis is often colonized with superantigen-releasing Staph. aureus, and application of a staphylococcal superantigen to human skin induces an eczematoid reaction.     

Chemokine networks in inflammatory skin diseases

The superfamily of chemokines comprises numerous small, cytokine-like chemotactic proteins, which have a fundamental role in the regulation of leukocyte trafficking. The chemokine-chemokine receptor system is highly redundant and promiscuous, and forms a complex network relevantly involved in the expression of chronic inflammatory skin diseases, including allergic contact dermatitis, atopic dermatitis and psoriasis. The pattern of chemokine expression shows overlapping features but also important differences in these diseases due to distinct sources and types of pro-inflammatory signals involved in chemokine induction, and the inherent capacity of resident skin cells to produce chemokines. Chemokine receptors (G-protein coupled receptors) rather than chemokines appear the appropriate therapeutic targets as they are more chemically tractable and play less redundant functions.     

Helicobacter pylori and inflammatory skin diseases

Throughout the history of mankind, infections have been the major cause of diseases. Over the last decades, not only the incidence of emerging infectious diseases have increased, but also tremendous strides have been made in understanding the biology of several pathogenic microorganisms. Helicobacter pylori(H. pylori) is a spiral-shaped, gram-negative bacterium, which infects over the half of the world's population. H. pylori has been implicated in the pathogenesis of a number of gastrointestinal disorders. However, new researches have demonstrated that H. pylori is also involved in the pathogenesis of various extragastric diseases. The difference in the clinical outcome of H. pylori infection may be explained, at least in part, by host response to the infection and H. pylori virulence factors. It is obvious that as developments in the research on H. pylori spring up, an understanding of the pathophysiology of H. pylori infection will continue to be identified. Here in this review, we summarize the current knowledge about H. pylori and its association with inflammatory skin diseases.     

Surfactant proteins in inflammatory skin diseases: controlled study

Surfactant proteins (SP) have recently been reported to be expressed in human skin tissue. SP is thought to play an essential role in the firstline defense of skin. In this study, we aimed to investigate if the SP may play a role in inflammatory skin diseases. Seven volunteers with psoriasis (n = 3), atopic dermatitis (n = 2), lichen planus (n = 1) and Behcet’s disease (n = 1) participated in the study. Biopsies from each lesion and adjacent (approximately 2 cm distant) normal-appearing skin in patients were performed. Expression and localization of the SP-A, -B, -C, and -D in fresh tissues were studied by an immunohistochemical technique. In all patients, there was a weak cytoplasmic staining with SP-A and SP-D and nuclear staining with SP-B and SP-C in the epidermis of normal-appearing skin samples. However, epidermal staining with SP was observed to be stronger in all lesional samples. In addition, there was a prominent staining in inflammatory cells infiltrating dermis. This expression represents a previously unknown immunologic response in the inflammatory skin diseases and may represent an important step in the pathogenesis of these disorders.     

Expression of cathepsin L and its inhibitor hurpin in inflammatory and neoplastic skin diseases

Cathepsin (Cat) L is an important lysosomal proteinase involved in a variety of cellular functions including intracellular protein turnover, epidermal homeostasis and hair development. Hurpin (serpinB13) is a cross-class specific serine protease inhibitor of Cat L. We have analysed the expression and localization of Cat L and hurpin in various inflammatory and neoplastic diseases by immunohistochemistry. Whereas Cat L expression in normal skin was below detection limit, immunoreactivity was detected in chronic inflammatory dermatoses. The highest expression of Cat L was found in psoriasis, atopic eczema and squamous cell carcinoma (SCC) samples. Samples of Lupus erythematosus, folliculitis, acne inversa, chronic leg ulcers and pyoderma gangrenosum demonstrated similar but lower expression for Cat L. In malignant cells of SCC, basal cell carcinoma and malignant melanoma, characteristic staining patterns were observed for Cat L, with more abundant expression at the periphery of the tumor. Expanding our previous work, we found that the expression of hurpin was confined mainly to the basal layer in normal skin samples, whereas hurpin was overexpressed and redistributed in diseased skin. The localization of hurpin in dermatoses and neoplasias differed from that in normal skin in that the highest expression was found in the outermost layers of the granular and upper spinous layers. Similarly to Cat L, the highest expression for hurpin was found in psoriasis and SCC. The results presented here summarize for the first time the expression of the protease Cat L and its inhibitor hurpin in a broad spectrum of skin diseases.     

microRNA在炎症性皮肤病中作用的研究进展

【摘要】 microRNA（miRNA）是一类转录后调控基因表达的非编码RNA分子,参与皮肤各种病理生理过程。近年来,miRNA表达谱的变化已被报道与部分炎症性皮肤病相关,例如miR-203、miR-146a、miR-21在银屑病皮损中表达上调;miR-155、miR-146a在特应性皮炎皮损中表达上调;miR-21、miR-223、miR-142-3p、miR142-5p在过敏性接触性皮炎皮损表达上调;而miR-146a、miR-155在系统性红斑狼疮患者外周血表达下调;miR-223在皮肌炎皮损中表达下调等。本文综述miRNA与部分炎症性皮肤病发生、发展之间的联系。