半乳糖凝集素与皮肤病研究进展

半乳糖凝集素家族是一类内源性凝集素家族,与含β-半乳糖苷残基的多聚糖具有高亲和力,目前已有15个半乳糖凝集素家族成员被发现,其广泛分布于上皮细胞和免疫细胞,参与细胞的生长分化、细胞间的粘附、细胞信号转导及细胞凋亡等多种细胞活动。其中,半乳糖凝集素-1,-3,-7,-9,-12参与皮肤肿瘤、创面愈合、银屑病、硬皮病、系统性红斑狼疮、特应性皮炎、白癜风等多种皮肤病的疾病进程,有望作为疾病发展和预后的生物标记物。本文对近年来半乳糖凝集素-1,-3,-7,-9,-12及相关皮肤病研究进展进行综述。     

Schwann cells as underestimated,major players in human skin physiology and pathology

Schwann cells (SCs) have long been recognized for their ability to support repair and promote axon regeneration following injury to the peripheral nervous system. In response to nerve injury, they rapidly dedifferentiate into a precursor-like state, secrete an array of inflammatory mediators and growth factors, proliferate, undergo epithelial-to-mesenchymal-like transformation to facilitate migration, phagocytose cellular debris and remodel the extracellular environment to promote regeneration of axons through the site of injury. However, even though a cutaneous role for SCs is becoming increasingly recognized, we argue in this Viewpoint essay that the likely complex functions of SCs in skin physiology and pathology beyond skin sensation and nerve repair deserve more attention and systemic research than they have received so far. For example, SCs promote wound healing, disseminate infection in leprosy, support the growth of neurofibromas/schwannomas and facilitate/accelerate the growth and invasion of melanoma. Despite representing a major dermal cell population, comparatively little is still known about the role of SCs in other dermatoses. To quintessentially illustrate the opportunities that promise to arise from a new skin research focus on SCs, we focus on two dermatoses that are not traditionally associated with SCs, that is, psoriasis and atopic dermatitis (AD), since both show distinct SC changes along with continuous nerve fibre degeneration and regeneration, and an impact of denervation on skin lesions. Specifically, we critically discuss the hypothesis that repeated activation of the SC repair programme occurs in and contributes to psoriasis and AD and delineate experimental approaches how to probe this clinically relevant hypothesis.     

主观皮肤类型与皮肤屏障功能的关系

目的:比较不同主观皮肤类型(油性、中性和干性皮肤)屏障功能指标的差异。方法:利用无创性方法对自评为油性、中性和干性皮肤的20~25岁北京城市女性(各30例)进行皮脂分泌率(SER)、角质层含水量、p H值和经皮肤水分丢失(TEWL)值的检测,并采用胶带连续粘脱后监测TEWL值变化的方法评价角质层完整性,采用角质层取样蛋白定量的方法评价角质层黏合力和丝氨酸蛋白酶活性。结果:主观皮肤类型为中性皮肤者具有最佳的屏障功能;干性皮肤和油性皮肤者面颊部的屏障功能均有不同程度的受损,表现为TEWL值明显升高、p H值升高、丝氨酸蛋白酶活性增加;但二者也有区别,油性皮肤者角质层完整性下降更明显,而干性皮肤主要是角质层黏合力明显减弱。结论:自评为油性和干性皮肤者与中性皮肤者相比,屏障功能均存在一定程度的缺陷,油性皮肤与干性皮肤均具有不同特点,且与其屏障受损的机制不同有关。     

Matrix remodelling and MMP expression/activation are associated with hidradenitis suppurativa skin inflammation

Hidradenitis suppurativa/acne inversa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle, associated with considerable tissue remodelling. Although abnormal cytokine expression was detected both in perilesional and in uninvolved skin, up to now there is no model allowing a better understanding of the implicit inflammatory mechanisms in HS. The aim of this study was to investigate the inflammatory response in HS skin by mean of an ex vivo model culture. To that purpose, nine skin biopsy specimens from patients suffering from HS and controls were cultured up to 4 days. Microscopy imaging investigations showed variations of collagen I and III organization, and an increase in elastin fibres fragmentation in HS skin after 4 days of culture. The HS matrix structure remodelling was associated with high level of MMP‐2 and MMP‐9 in HS lesional skin. After 4 days of culture, the MMP expression in HS perilesional skin reached the level observed in HS lesional skin. Concomitantly, an increase in IL‐1β concentration was observed in all skin samples after 4 days of culture, although IL‐1β concentrations remained significantly higher in HS lesional skin as compared with control skin. Meanwhile, neither IL‐17 concentrations nor the inflammasome components NLRP3 and caspase‐1 varied. Thus, our HS skin model culture showed that MMP‐induced matrix alteration could participate in HS inflammation by releasing biological active peptides and inflammatory factors from the extracellular matrix (ECM), and open new opportunities to investigate the regulation of the inflammatory mechanism associated with HS.     

表皮通透屏障功能对皮肤的调节作用及意义

表皮通透屏障功能除调节水分经表皮进出机体外,还对皮肤的其他生物功能如炎症、表皮增生、pH及离子的分布等也具有重要地调节作用。而且,维持表皮通透屏障功能在最佳水平有利于预防某些皮肤病的发生;改善皮肤屏障功能有助于某些皮肤病的治疗。     

Changes in skin physiology during bath PUVA therapy

BACKGROUND: Frequent bathing leads to a skin barrier damage with various changes in physiological skin parameters. Conversely, ultraviolet (UV) irradiation may improve the impaired skin barrier by reducing inflammatory reactions. OBJECTIVES: The aim of this study was to investigate the changes of physiological skin parameters during a therapy with 8-methoxypsoralen (8-MOP) bathing and subsequent UVA irradiation. METHODS: Thirty patients with a skin disease without barrier disruption were treated with daily bathing in a 8-MOP solution (0.0005%) and subsequent UVA irradiation. Multiple physiological skin parameters (transepidermal water loss, skin blood flow, skin colour, sebum content, skin hydration) were measured repeatedly on clinically non-affected skin on the back, forearm and forehead. In addition, patch testing with sodium lauryl sulphate (SLS) (0.5%) was performed on the forearm and on the back. RESULTS: We found a moderate but significant disturbance of skin barrier and hydration on the forearm and the back (bathing + irradiation) after increasing dosages of therapy. In addition, SLS testing leads to stronger reactions. CONCLUSIONS: We conclude that on clinically healthy skin the impairment of skin barrier by frequent bathing cannot be completely compensated by subsequent UVA irradiation. When conducting a treatment with 8-MOP bathing and UVA irradiation a concomitant therapy supporting the recovery of skin barrier, e.g. with moisturizer, should be performed.     

The sirtuin 6: An overture in skin cancer

In the recent past, the sirtuins have been under intense investigation for their roles in biology and disease, including cancer. The sirtuin SIRT6 is comparatively a lesser studied member of this family of seven proteins. Like certain other sirtuins, SIRT6 is emerging to have an oncogenic function as well as tumor suppressor roles in cancer. Limited studies have been conducted assessing the role and functional significance of SIRT6 in melanoma and non-melanoma skin cancers. In this review, we have attempted to critically dissect the potential role and significance of SIRT6 in skin carcinogenesis. With limited available information to date, SIRT6 appears to have a pro-proliferative function in non-melanoma skin cancers (NMSCs), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In addition, SIRT6 is also emerging to have an oncogenic function in melanoma. Moreover, we have provided information regarding the available SIRT6 inhibitors. Conclusively, it appears that additional comprehensive studies are needed to establish the role of SIRT6 in skin biology and skin diseases, including cancer. Further, concerted efforts are needed to characterize the stage-specific role of SIRT6 in skin cancers.     

Transgenic expression of human amphiregulin in mouse skin: inflammatory epidermal hyperplasia and enlarged sebaceous glands

To explore the role of amphiregulin in inflammatory epidermal hyperplasia, we overexpressed human AREG (hAREG) in FVB/N mice using a bovine K5 promoter. A construct containing AREG coding sequences flanked by 5′ and 3′ untranslated region sequences (AREG‐UTR) led to a >10‐fold increase in hAREG expression compared to an otherwise‐identical construct containing only the coding region (AREG‐CDR). AREG‐UTR mice developed tousled, greasy fur as well as elongated nails and thickened, erythematous tail skin. No such phenotype was evident in AREG‐CDR mice. Histologically, AREG‐UTR mice presented with marked epidermal hyperplasia of tail skin (2.1‐fold increase in epidermal thickness with a 9.5‐fold increase in Ki‐67⁺ cells) accompanied by significantly increased CD4+ T‐cell infiltration. Dorsal skin of AREG‐UTR mice manifested lesser but still significant increases in epidermal thickness and keratinocyte hyperplasia. AREG‐UTR mice also developed marked and significant sebaceous gland enlargement, with corresponding increases in Ki‐67⁺ cells. To determine the response of AREG‐UTR animals to a pro‐inflammatory skin challenge, topical imiquimod (IMQ) or vehicle cream was applied to dorsal and tail skin. IMQ increased dorsal skin thickness similarly in both AREG‐UTR and wild type mice (1.7‐ and 2.2‐fold vs vehicle, P < 0.001 each), but had no such effect on tail skin. These results confirm that keratinocyte expression of hAREG elicits inflammatory epidermal hyperplasia, and are consistent with prior reports of tail epidermal hyperplasia and increased sebaceous gland size in mice expressing human epigen.     

Nicotinamide and the skin

Nicotinamide, an amide form of vitamin B3, boosts cellular energy and regulates poly‐ADP‐ribose‐polymerase 1, an enzyme with important roles in DNA repair and the expression of inflammatory cytokines. Nicotinamide shows promise for the treatment of a wide range of dermatological conditions, including autoimmune blistering disorders, acne, rosacea, ageing skin and atopic dermatitis. In particular, recent studies have also shown it to be a potential agent for reducing actinic keratoses and preventing skin cancers.     

The role of mitogen- and stress-activated protein kinase 1 and 2 in chronic skin inflammation in mice

Mitogen- and stress-activated protein kinase 1 and 2 (MSK1/2) are two kinases phosphorylated by both ERK1/2 and p38 MAPK. Recently, MSK1 and 2 have been reported to act as negative regulators of acute inflammation. In this study, we investigated the role of MSK1/2 in chronic skin inflammation using an oxazolone-induced allergic contact dermatitis model in MSK1/2 knockout mice and wild-type mice. MSK1/2 knockout mice were demonstrated to have significantly increased inflammation compared with wild-type mice. This was measured by an increased ear thickness, elevated infiltration of neutrophils in the skin and increased inflammatory histological changes. Furthermore, we found significantly elevated levels of the proinflammatory cytokines Tumor necrosis factor-α (TNF-α), IL-1β and IL-6 at both mRNA and protein levels in MSK1/2 knockout mice compared with wild-type mice after oxazolone treatment. In addition, the mRNA expression of the chemokine Thymus and activation regulated chemokine (TARC) was demonstrated to be significantly elevated in oxazolone-treated MSK1/2 knockout mice compared with wild-type mice. The increased expression of TARC was paralleled by increased infiltration of cells positive for the TARC receptor, CCR4, in the dermis of MSK1/2 knockout mice. Our results indicate that MSK1/2 are involved in the activation of feedback mechanisms that dampen oxazolone-induced skin inflammation.     

Assessment of skin lesions and skin cancer using simple electrical impedance indices

Background/aims: Purpose of this investigation was to assess benign pigmented cellular nevus (BEN), basal cell carcinoma (BCC), dermatofibroma (DER), dysplastic nevus (DYS), and seborrheic keratoses (SEB) using in vivo non- invasive electrical impedance technique.
Methods: Electrical impedance was measured at 258 BEN, 34 BCC, 17 DER, 35 DYS, and 26 SEB lesions. Controls were measured at healthy skin close to the lesions. The impedance was measured between 1 kHz and 1 MHz at five depth settings. After the impedance measurements the lesions were histopathologically diagnosed. The impedance spectra were parameterized to four indices prior to the statistical analysis of the data.
Results: There were significant differences between the lesions and their controls for BEN ( P  < 0.001), BCC ( P  < 0.001), DYS ( P  < 0.01), and SEB ( P  < 0.01).
Conclusions: There are clear statistical differences between impedance of common lesions and control skin. With some further developments, the impedance technique can be useful as a diagnostic decision support tool for skin cancer assessment.     

Mammalian SIRT2 inhibits keratin 19 expression and is a tumor suppressor in skin

SIRT2 is a member of the mammalian sirtuin family (SIRT1‐7). As compared with other sirtuins, SIRT2 is found primarily in the cytoplasm. It regulates multiple physiological processes. However, the precise role of SIRT2 in skin cancer remains unclear. Here, we show that SIRT2 is downregulated in human skin cancer as compared with normal skin. SIRT2 deletion increases tumor growth in mice. SIRT2 knockdown upregulates the stem cell marker Keratin 19 (K19) in keratinocytes. In mice, SIRT2 deletion up‐regulates K19 and K15 while it down‐regulates the differentiation marker Loricrin in both normal skin and tumors. In skin tumors but not normal skin, SIRT2 deletion up‐regulates the stem cell marker CD34 and increases the number of Ki67‐positive cells. These findings indicate that SIRT2 is a tumor suppressor in the skin. Our findings add new insights into the role of SIRT2 in the molecular pathogenesis of skin cancer.     

The relationship between skin function,barrier properties,and body‐dependent factors

Background

Skin is a multilayer interface between the body and the environment, responsible for many important functions, such as temperature regulation, water transport, sensation, and protection from external triggers.

Objectives

This paper provides an overview of principal factors that influence human skin and describes the diversity of skin characteristics, its causes and possible consequences. It also discusses limitations in the barrier function of the skin, describing mechanisms of absorption.

Methods

There are a number of in vivo investigations focusing on the diversity of human skin characteristics with reference to barrier properties and body‐dependent factors.

Results

Skin properties vary among individuals of different age, gender, ethnicity, and skin types. In addition, skin characteristics differ depending on the body site and can be influenced by the body‐mass index and lifestyle. Although one of the main functions of the skin is to act as a barrier, absorption of some substances remains possible.

Conclusions

Various factors can alter human skin properties, which can be reflected in skin function and the quality of everyday life. Skin properties and function are strongly interlinked.