Skin as an endocrine organ: A narrative review.
Indian journal of dermatology, venereology and leprology
Skin being the largest organ of the body, is equipped with numerous functional properties. Over the past few years, intricate research into the biology of skin has led to a gamut of discoveries. Skin is now regarded as one of the most vital endocrine organs. The skin contains equivalents of the hypothalamo-pituitary-adrenal axis, hypothalamo-pituitary-thyroid axis and the appendages produce multiple hormones such as Vitamin D, sex steroids, retinoids and opioids. In this article, we will explore the role of skin as a target and source of some of the hormones of the human body, and briefly touch on the clinical applications.
10.25259/IJDVL_533_2021
Cystatins--Extra- and intracellular cysteine protease inhibitors: High-level secretion and uptake of cystatin C in human neuroblastoma cells.
Wallin Hanna,Bjarnadottir Maria,Vogel Lotte K,Wassélius Johan,Ekström Ulf,Abrahamson Magnus
Biochimie
Cystatins are present in mammals, birds, fish, insects, plants, fungi and protozoa and constitute a large protein family, with most members sharing a cysteine protease inhibitory function. In humans 12 functional cystatins exist, forming three groups based on molecular organisation and distribution in the organism. The type 1 cystatins (A and B) are known as intracellular, type 2 cystatins (C, D, E/M, F, G, S, SN and SA) extracellular and type 3 cystatins (L- and H-kininogen) intravascular proteins. The present paper is focused on the human cystatins and especially those of type 2, which are directed (with signal peptides) for cellular export following translation. Results indicating existence of systems for significant internalisation of type 2 cystatins from the extracellular to intracellular compartments are reviewed. Data showing that human neuroblastoma cell lines generally secrete high levels, but also contain high amounts of cystatin C are presented. Culturing of these cells in medium containing cystatin C at concentrations found in body fluids resulted in increased intracellular cystatin C, as a result of an uptake process. At immunofluorescence cytochemistry a pronounced vesicular cystatin C staining was observed. The simplistic denotation of the type 2 cystatins as extracellular inhibitors is thus challenged, and possible biological functions of the internalised cystatins are discussed. To illustrate the special case of high cellular cystatin content seen in cells of patients with hereditary cystatin C amyloid angiopathy, expression vectors for wild-type and L68Q mutated cystatin C were used to transfect SK-N-BE(2) cells. Clones overexpressing the two variants showed increased secreted levels of cystatin C. Within the cells the L68Q variant appeared to mainly localise to the endoplasmic reticulum rather than to acidic vesicular organelles, indicating limitations in the transport out from the cell rather than increased uptake as explanation for the elevated cellular cystatin levels seen in hereditary cystatin C amyloid angiopathy.
10.1016/j.biochi.2010.08.011
Cystatin A suppresses ultraviolet B-induced apoptosis of keratinocytes.
Takahashi Hidetoshi,Komatsu Naritsuna,Ibe Masaki,Ishida-Yamamoto Akemi,Hashimoto Yoshio,Iizuka Hajime
Journal of dermatological science
BACKGROUND:Cystatin A is a cysteine proteinase inhibitor abundantly expressed in keratinocytes. Although cystatin A is one of the cornified cell envelope constituents and expressed in the upper epidermis, its precise function is still unknown. Ultraviolet B irradiation (UVB) induces apoptosis accompanied with the activation of cysteine proteinases, caspases. OBJECTIVE:We investigated the effect of cystatin A on UVB-induced apoptosis of keratinocytes. METHODS:We assessed the caspase activities and apoptotic cell numbers induced by UVB ittadiation in cystatin A gene transfected keratinocytes. RESULTS:UVB-induced pro-caspase 3 cleavage and caspase 3 activation were suppressed in cystatin A expression vector-transfected SV40-transformed human keratinocytes (SVHK). Furthermore, the transfected SVHK cells were resistant to UVB-induced apoptosis. In contrast neither caspase 8 nor caspase 9 activities were affected by UVB irradiation in cystatin A-transfected SVHK cells. The effects were also observed in cystatin A expression adenovirus vector-transfected cultured normal human keratinocytes (NHK). Conversely knockdown of cystatin A by si-RNA induced marked apoptosis of NHK cells following UVB irradiation accompanied with increased caspase 3 activity. In order to confirm the antiapoptotic effect of cystatin A in vivo UVB irradiation was performed on cystatin A transgenic mice (cystatin A-tg). The epidermis from cystatin A-tg was resistant to UVB-induced apoptosis compared to control mice epidermis. CONCLUSION:These results indicate that cystatin A suppresses UVB-induced apoptosis of keratinocytes by the inhibition of caspase 3 activation.
10.1016/j.jdermsci.2007.02.003
Cell-to-cell interactions in bone.
Stains Joseph P,Civitelli Roberto
Biochemical and biophysical research communications
Bone development (modeling) occurs by migration, aggregation, and condensation of immature osteo/chondroprogenitor cells to form the cartilaginous anlage. This process requires precisely controlled cell-cell interactions. Likewise, bone remodeling in the adult skeleton is a dynamic process that requires coordinated cellular activities among osteoblasts, osteocytes, and osteoclasts to maintain bone homeostasis. The cooperative nature of both bone modeling and remodeling requires tightly regulated mechanisms of intercellular recognition and communication that permit the cells to sort and migrate, synchronize activity, equalize hormonal responses, and diffuse locally generated signals. Osteoblasts and osteocytes achieve these interactions through cadherin-based adherens junctions as well as by formation of communicating junctions, gap junctions. This review examines the current knowledge of how direct cell-to-cell interactions modulate osteoblast function.
10.1016/j.bbrc.2004.11.078
Osteoporosis in Skin Diseases.
International journal of molecular sciences
Osteoporosis (OP) is defined as a generalized skeletal disease characterized by low bone mass and an alteration of the microarchitecture that lead to an increase in bone fragility and, therefore, an increased risk of fractures. It must be considered today as a true public health problem and the most widespread metabolic bone disease that affects more than 200 million people worldwide. Under physiological conditions, there is a balance between bone formation and bone resorption necessary for skeletal homeostasis. In pathological situations, this balance is altered in favor of osteoclast (OC)-mediated bone resorption. During chronic inflammation, the balance between bone formation and bone resorption may be considerably affected, contributing to a net prevalence of osteoclastogenesis. Skin diseases are the fourth cause of human disease in the world, affecting approximately one third of the world's population with a prevalence in elderly men. Inflammation and the various associated cytokine patterns are the basis of both osteoporosis and most skin pathologies. Moreover, dermatological patients also undergo local or systemic treatments with glucocorticoids and immunosuppressants that could increase the risk of osteoporosis. Therefore, particular attention should be paid to bone health in these patients. The purpose of the present review is to take stock of the knowledge in this still quite unexplored field, despite the frequency of such conditions in clinical practice.
10.3390/ijms21134749
Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research.
Shane Elizabeth,Burr David,Ebeling Peter R,Abrahamsen Bo,Adler Robert A,Brown Thomas D,Cheung Angela M,Cosman Felicia,Curtis Jeffrey R,Dell Richard,Dempster David,Einhorn Thomas A,Genant Harry K,Geusens Piet,Klaushofer Klaus,Koval Kenneth,Lane Joseph M,McKiernan Fergus,McKinney Ross,Ng Alvin,Nieves Jeri,O'Keefe Regis,Papapoulos Socrates,Sen Howe Tet,van der Meulen Marjolein C H,Weinstein Robert S,Whyte Michael,
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management.
10.1002/jbmr.253
Dermal Fibroblast Heterogeneity and Its Contribution to the Skin Repair and Regeneration.
Xue Meilang,Zhao Ruilong,March Lyn,Jackson Christopher
Advances in wound care
Dermal fibroblasts are the major cell type in the skin's dermal layer. These cells originate from distinct locations of the embryo and reside in unique niches in the dermis. Different dermal fibroblasts exhibit distinct roles in skin development, homeostasis, and wound healing. Therefore, these cells are becoming attractive candidates for cell-based therapies in wound healing. Human skin dermis comprises multiple fibroblast subtypes, including papillary, reticular, and hair follicle-associated fibroblasts, and myofibroblasts after wounding. Recent studies reveal that these cells play distinct roles in wound healing and contribute to diverse healing outcomes, including nonhealing chronic wound or excessive scar formation, such as hypertrophic scars (HTS) and keloids, with papillary fibroblasts having antiscarring and reticular fibroblast scar-forming properties. The identities and functions of dermal fibroblast subpopulations in many respects remain unknown. In this review, we summarize the current understanding of dermal fibroblast heterogeneity, including their defined cell markers and dermal niches, dynamic changes, and contributions to skin wound healing, with the emphasis on scarless healing, healing with excessive scars (HTS and keloids), chronic wounds, and the potential application of this heterogeneity for developing cell-based therapies that allow wounds to heal faster with less scarring. Heterogeneous dermal fibroblast populations and their functions are poorly characterized. Refining and advancing our understanding of dermal fibroblast heterogeneity and their participation in skin homeostasis and wound healing may create potential therapeutic applications for nonhealing chronic wounds or wounds that heal with excessive scarring.
10.1089/wound.2020.1287
Immunohistochemical localization of cathepsin L and cystatin A in normal skin and skin tumors.
Palungwachira Piti,Kakuta Mie,Yamazaki Masashi,Yaguchi Hitoshi,Tsuboi Ryoji,Takamori Kenji,Ogawa Hideoki
The Journal of dermatology
Cathepsin L, a cysteine proteinase, and cystatin A, an inhibitor of cysteine proteinases, are thought to regulate the invasion and metastasis of malignant cells. In this study, the expression of cathepsin L and cystatin A in skin tumors was investigated immunohistochemically in order to examine the relationship between these two enzymes in the pathophysiology of malignant cells. Formalin-fixed and paraffin embedded specimens from normal skin, seborrheic keratoses, and squamous cell carcinomas were reacted with polyclonal antibodies against rat cathepsin L or cystatin a which cross-react to human cathepsin L and cystatin A, respectively. The consequent immunostaining of these enzymes was observed to be strong in normal skin (4 cases) and seborrheic keratosis (6 cases). In well-differentiated squamous cell carcinoma (SCC) (9 cases), staining for cathepsin L and cystatin A was moderately positive in differentiated tumor cells and negative in undifferentiated SCC (5 cases). The degree of staining of these enzymes was inversely correlated with the differentiation of the malignant cells. These results suggest that the immunohistochemical analysis of cathepsin L and cystatin A is a useful indicator for an aspect of malignancy in human epidermal keratinocytes.
Cystatin superfamily.
Ochieng Josiah,Chaudhuri Gautam
Journal of health care for the poor and underserved
Cystatins, the classical inhibitors of C1 cysteine proteinases, have been extensively studied and reviewed in the literature. Over the last 20 years, however, proteins containing cystatin domains but lacking protease inhibitory activities have been identified, and most likely more will be described in the near future. These proteins together with family 1, 2, and 3 cystatins constitute the cystatin superfamily. Mounting evidence points to the new roles that some members of the superfamily have acquired over the course of their evolution. This review is focused on the roles of cystatins in: 1) tumorigenesis, 2) stabilization of matrix metalloproteinases, 3) glomerular filtration rate, 4) immunomodulation, and 5) neurodegenerative diseases. It is the goal of this review to get as many investigators as possible to take a second look at the cystatin superfamily regarding their potential involvement in serious human ailments.
10.1353/hpu.0.0257
Skin chronological aging drives age-related bone loss via secretion of cystatin-A.
Nature aging
Although clinical evidence has indicated an association between skin atrophy and bone loss during aging, their causal relationship and the underlying mechanisms are unknown. Here we show that premature skin aging drives bone loss in mice. We further identify that cystatin-A (Csta), a keratinocyte-enriched secreted factor, mediates the effect of skin on bone. Keratinocyte-derived Csta binds the receptor for activated C-kinase 1 in osteoblast and osteoclast progenitors, thus promoting their proliferation but inhibiting osteoclast differentiation. Csta secretion decreases with skin aging in both mice and humans, thereby causing senile osteoporosis by differentially decreasing the numbers of osteoblasts and osteoclasts. In contrast, topical application of calcipotriol stimulates Csta production in the epidermis and alleviates osteoporosis. These results reveal a mode of endocrine regulation of bone metabolism in the skin, and identify Csta as an epidermally derived hormone linking skin aging to age-related bone loss. Enhancers of skin Csta levels could serve as a potential topical drug for treatment of senile osteoporosis.
10.1038/s43587-022-00285-x
Cystatin A inhibits IL-8 production by keratinocytes stimulated with Der p 1 and Der f 1: biochemical skin barrier against mite cysteine proteases.
Kato Takeshi,Takai Toshiro,Mitsuishi Kouichi,Okumura Ko,Ogawa Hideoki
The Journal of allergy and clinical immunology
BACKGROUND:Der p 1 and Der f 1 are the most immunodominant allergens produced by house dust mites and are suspected to be involved in the pathogenesis of allergy through their cysteine protease activity. However, stimulation of keratinocytes by these protease allergens and protective systems in the skin against them have not been well investigated. OBJECTIVE:We purified and identified the dominant skin-derived inhibitor against the proteolytic activities of these allergens and analyzed its effect on keratinocyte activation. METHODS:Recombinant allergens were used for the experiments. We analyzed whether human sweat inhibits the enzymatic activities of Der p 1 and Der f 1 and used sweat as the skin-derived material to isolate the inhibitor. The inhibitor was purified by means of column chromatography and subsequently identified by means of protein sequencing and immunoblotting. Keratinocytes were stimulated with the allergens in the absence or presence of the inhibitor, and the concentration of secreted IL-8 was measured. RESULTS:Sweat inhibited the proteolytic activities of Der p 1 and Der f 1. The sweat inhibitor was identified as cystatin A. The stimulation of normal human keratinocytes and the human keratinocyte cell line HaCaT with these protease allergens upregulated IL-8 secretion, and addition of cystatin A blocked this upregulation. Normal human keratinocytes secreted cystatin A into the medium. CONCLUSIONS:The proteolytic activity of Der p 1 and Der f 1 stimulates human keratinocytes in vitro. Cystatin A produced by keratinocytes is the dominant biochemical skin barrier that eliminates the enzymatic activity of these mite cysteine proteases and prevents them from stimulating keratinocytes.
10.1016/j.jaci.2005.03.044
Anatomy, histology and immunohistochemistry of normal human skin.
Kanitakis Jean
European journal of dermatology : EJD
The skin is the largest organ of the body, accounting for about 15% of the total body weight in adult humans. It exerts multiple vital protective functions against environmental aggressions, rendered possible thanks to an elaborate structure, associating various tissues of ectodermal and mesodermal origin, arranged in three layers, including (from top to bottom) the epidermis (and its appendages), the dermis and the hypodermis. This article reviews the main data concerning the anatomy, histology and immunohistochemistry of normal human skin.
Cytokinocytes: the diverse contribution of keratinocytes to immune responses in skin.
Jiang Yanyun,Tsoi Lam C,Billi Allison C,Ward Nicole L,Harms Paul W,Zeng Chang,Maverakis Emanual,Kahlenberg J Michelle,Gudjonsson Johann E
JCI insight
The skin serves as the primary interface between our body and the external environment and acts as a barrier against entry of physical agents, chemicals, and microbes. Keratinocytes make up the main cellular constitute of the outermost layer of the skin, contributing to the formation of the epidermis, and they are crucial for maintaining the integrity of this barrier. Beyond serving as a physical barrier component, keratinocytes actively participate in maintaining tissue homeostasis, shaping, amplifying, and regulating immune responses in skin. Keratinocytes act as sentinels, continuously monitoring changes in the environment, and, through microbial sensing, stretch, or other physical stimuli, can initiate a broad range of inflammatory responses via secretion of various cytokines, chemokines, and growth factors. This diverse function of keratinocytes contributes to the highly variable clinical manifestation of skin immune responses. In this Review, we highlight the highly diverse functions of epidermal keratinocytes and their contribution to various immune-mediated skin diseases.
10.1172/jci.insight.142067
Molecular cloning of mouse epidermal cystatin A and detection of regulated expression in differentiation and tumorigenesis.
Hawley-Nelson P,Roop D R,Cheng C K,Krieg T M,Yuspa S H
Molecular carcinogenesis
A gamma gt 11 cDNA expression library representing mouse epidermis mRNA was screened with polyclonal rabbit antiserum directed against 10-13 kDa epidermal antigens that had previously been shown to be regulated during epidermal differentiation. A cDNA clone was detected and isolated and its identity as the coding sequence for one of the antigens was confirmed by translation of hybrid-selected mRNA from mouse epidermis. The cDNA sequence predicted a peptide homologous to the reported sequence of rat epidermis cystatin A, a thiol proteinase inhibitor. This identification was confirmed by cross-reactivity of the gamma clone fusion protein with authentic antiserum to rat epidermis cystatin A. Southern gel analysis showed that mouse DNA may contain several closely related genes homologous to the cystatin probe. An mRNA of about 0.6 kb from epidermis and cultured mouse epidermal cells hybridized with the cystatin probe on northern analysis. The abundance of the message was high in cultured basal cells and was selectively diminished by inducing terminal differentiation in culture with an elevated Ca2+ concentration in the medium. Cystatin message was abundant in chemically induced mouse skin papillomas but reduced in carcinomas. In epidermis, mRNA was localized to the less differentiated basal and lower spinous layers by in situ hybridization. Regulation of expression of cystatin A in epidermis and tumors suggests that it may be important in the control of normal keratinocyte proliferation and differentiation and in malignant conversion.
10.1002/mc.2940010309
Cell aging and cellular senescence in skin aging - Recent advances in fibroblast and keratinocyte biology.
Gruber Florian,Kremslehner Christopher,Eckhart Leopold,Tschachler Erwin
Experimental gerontology
The aging of the skin is the most visible and obvious manifestation of organismal aging and may serve as a predictor of life expectancy and health. It is, however, also the human desire for long-lasting beauty that further raises interests in the topic, and thus considerable means and efforts are put into studying the mechanisms of skin aging in basic and applied research. Both medical und non-medical interests are of benefit for skin research in general because the results from these studies help to deepen our understanding of the complex molecular, biological, cell signaling, developmental and immunological processes in this organ. In fact, the skin is an ideal organ to observe and analyze the impact of extrinsic and intrinsic drivers of aging. Within the past five years technological advances like lineage tracing of cells in model organisms, intra-vital microscopy, nucleic acid sequencing at the single cell level, and high resolution mass spectrometry have allowed to study aging and senescence of individual skin cells within the tissue context, their signaling and communication, and to derive new hypotheses for experimental studies in vitro. In this short review we will discuss very recent developments that promise to extend the existing knowledge on cell aging and senescence of dermal fibroblasts and epidermal keratinocytes in skin aging.
10.1016/j.exger.2019.110780
Vitamin D and cancer: a review of molecular mechanisms.
Fleet James C,DeSmet Marsha,Johnson Robert,Li Yan
The Biochemical journal
The population-based association between low vitamin D status and increased cancer risk can be inconsistent, but it is now generally accepted. These relationships link low serum 25OHD (25-hydroxyvitamin D) levels to cancer, whereas cell-based studies show that the metabolite 1,25(OH)2D (1,25-dihydroxyvitamin D) is a biologically active metabolite that works through vitamin D receptor to regulate gene transcription. In the present review we discuss the literature relevant to the molecular events that may account for the beneficial impact of vitamin D on cancer prevention or treatment. These data show that although vitamin D-induced growth arrest and apoptosis of tumour cells or their non-neoplastic progenitors are plausible mechanisms, other chemoprotective mechanisms are also worthy of consideration. These alternative mechanisms include enhancing DNA repair, antioxidant protection and immunomodulation. In addition, other cell targets, such as the stromal cells, endothelial cells and cells of the immune system, may be regulated by 1,25(OH)2D and contribute to vitamin D-mediated cancer prevention.
10.1042/BJ20110744
The skin as a metabolic and immune-competent organ: Implications for drug-induced skin rash.
Sharma Amy,Saito Yoshiro,Hung Shuen-Iu,Naisbitt Dean,Uetrecht Jack,Bussiere Jeanine
Journal of immunotoxicology
Current advances in the study of cutaneous adverse drug reactions can be attributed to the recent understanding that the skin is both a metabolically and immunologically competent organ. The ability of the skin to serve as a protective barrier with limited drug biotransformation ability, yet highly active immune function, has provided insights into its biological capability. While the immune response of the skin to drugs is vastly different from that of the liver due to evolutionary conditioning, it frequently occurs in response to various drug classes and manifests as a spectrum of hypersensitivity reactions. The skin is a common site of adverse and idiosyncratic drug reactions; drug-specific T-cells, as well as involvement of an innate immune response, appear to be key mechanistic drivers in such scenarios. Association of other factors such as human leukocyte antigen (HLA) polymorphisms may play a significant role for particular drugs. This review aims to integrate emerging findings into proposed mechanisms of drug metabolism and immunity in the skin that are likely responsible for rashes and other local allergic responses. These unique biological aspects of the skin, and their translation into implications for drug development and the use of animal models, will be discussed.
10.1080/1547691X.2018.1514444
Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.
Di Meglio Paola,Duarte João H,Ahlfors Helena,Owens Nick D L,Li Ying,Villanova Federica,Tosi Isabella,Hirota Keiji,Nestle Frank O,Mrowietz Ulrich,Gilchrist Michael J,Stockinger Brigitta
Immunity
Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanisms are largely unknown. Here we show that the aryl hydrocarbon receptor (AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists increased inflammation. Similarly, AhR signaling via the endogenous ligand FICZ reduced the inflammatory response in the imiquimod-induced model of skin inflammation and AhR-deficient mice exhibited a substantial exacerbation of the disease, compared to AhR-sufficient controls. Nonhematopoietic cells, in particular keratinocytes, were responsible for this hyperinflammatory response, which involved upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders.
10.1016/j.immuni.2014.04.019
Mutations in CSTA, encoding Cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion.
Blaydon Diana C,Nitoiu Daniela,Eckl Katja-Martina,Cabral Rita M,Bland Philip,Hausser Ingrid,van Heel David A,Rajpopat Shefali,Fischer Judith,Oji Vinzenz,Zvulunov Alex,Traupe Heiko,Hennies Hans Christian,Kelsell David P
American journal of human genetics
Autosomal-recessive exfoliative ichthyosis presents shortly after birth as dry, scaly skin over most of the body with coarse peeling of nonerythematous skin on the palms and soles, which is exacerbated by excessive moisture and minor trauma. Using whole-genome homozygosity mapping, candidate-gene analysis and deep sequencing, we have identified loss-of-function mutations in the gene for protease inhibitor cystatin A (CSTA) as the underlying genetic cause of exfoliative ichthyosis. We found two homozygous mutations, a splice-site and a nonsense mutation, in two consanguineous families of Bedouin and Turkish origin. Electron microscopy of skin biopsies from affected individuals revealed that the level of detachment occurs in the basal and lower suprabasal layers. In addition, in vitro modeling suggests that in the absence of cystatin A protein, there is a cell-cell adhesion defect in human keratinocytes that is particularly prominent when cells are subject to mechanical stress. We show here evidence of a key role for a protease inhibitor in epidermal adhesion within the lower layers of the human epidermis.
10.1016/j.ajhg.2011.09.001
Molecular Mechanisms of Cutaneous Inflammatory Disorder: Atopic Dermatitis.
Kim Jung Eun,Kim Jong Sic,Cho Dae Ho,Park Hyun Jeong
International journal of molecular sciences
Atopic dermatitis (AD) is a multifactorial inflammatory skin disease resulting from interactions between genetic susceptibility and environmental factors. The pathogenesis of AD is poorly understood, and the treatment of recalcitrant AD is still challenging. There is accumulating evidence for new gene polymorphisms related to the epidermal barrier function and innate and adaptive immunity in patients with AD. Newly-found T cells and dendritic cell subsets, cytokines, chemokines and signaling pathways have extended our understanding of the molecular pathomechanism underlying AD. Genetic changes caused by environmental factors have been shown to contribute to the pathogenesis of AD. We herein present a review of the genetics, epigenetics, barrier dysfunction and immunological abnormalities in AD with a focus on updated molecular biology.
10.3390/ijms17081234
Skin barrier immunity and ageing.
Chambers Emma S,Vukmanovic-Stejic Milica
Immunology
The skin is the outermost layer of the body with an extensive surface area of approximately 1·8 m , and is the first line of defence against a multitude of external pathogens and environmental insults. The skin also has important homeostatic functions such as reducing water loss and contributing to thermoregulation of the body. The structure of the skin and its cellular composition work in harmony to prevent infections and to deal with physical and chemical challenges from the outside world. In this review, we discuss how the structural cells such as keratinocytes, fibroblasts and adipocytes contribute to barrier immunity. We also discuss specialized immune cells that are resident in steady-state skin including mononuclear phagocytes, such as Langerhans cells, dermal macrophages and dermal dendritic cells in addition to the resident memory T cells. Ageing results in an increased incidence of cancer and skin infections. As we age, the skin structure changes with thinning of the epidermis and dermis, increased water loss, and fragmentation of collagen and elastin. In addition, the skin immune composition is altered with reduced Langerhans cells, decreased antigen-specific immunity and increased regulatory populations such as Foxp3 regulatory T cells. Together, these alterations result in decreased barrier immunity in the elderly, explaining in part their increased susceptiblity to cancer and infections.
10.1111/imm.13152
Calcium--a central regulator of keratinocyte differentiation in health and disease.
Elsholz Floriana,Harteneck Christian,Muller Walter,Friedland Kristina
European journal of dermatology : EJD
Regular keratinocyte differentiation is crucial for the formation of an intact epidermal barrier and is triggered by extracellular calcium. Disturbances of epidermal barrier formation and aberrant keratinocyte differentiation are involved in the pathophysiology of several skin diseases, such as psoriasis, atopic dermatitis, basal and squamous skin cancer, and genetic skin diseases such as Darier's disease and Olmstedt syndrome. In this review, we summarize current knowledge about the underlying molecular mechanisms of calcium-induced differentiation in keratinocytes. We provide an overview of calcium's genomic and non-genomic mechanisms to induce differentiation and discuss the calcium gradient in the epidermis, giving rise to cornified skin and lipid envelope formation. We focus on the calcium-sensing receptor, transient receptor potential channels, and STIM/Orai as the major constituents of calcium sensing and calcium entry in the keratinocytes. Finally, skin diseases linked to impaired differentiation will be discussed, paying special attention to disturbed TRP channel expression and TRP channel mutations.
10.1684/ejd.2014.2452
Tight junctions in skin inflammation.
Bäsler Katja,Brandner Johanna M
Pflugers Archiv : European journal of physiology
Inflammation of the skin is found after various external stimuli, e.g., UV radiation, allergen uptake, microbial challenge, or contact with irritants, as well as due to intrinsic, not always well-defined, stimuli, e.g., in autoimmune responses. Often, it is also triggered by a combination of both. The specific processes, which mean the kind of cytokines and immune cells involved and the extent of the reaction, depend not only on the trigger but also on the predisposition of the individual. Tight junctions (TJs) in the skin have been shown to form a barrier in the granular cell layer of the epidermis. Furthermore, TJ proteins were found in several additional epidermal layers. Besides barrier function, TJ proteins have been shown to be involved in proliferation, differentiation, cell-cell adhesion, and apoptosis in keratinocytes. In inflamed skin, TJ proteins are often affected. We summarize here the impact of skin inflammation on TJs, e.g., in various forms of dermatitis including atopic dermatitis, in skin infection, and in UV-irradiated skin, and discuss the role of TJs in these inflammatory processes.
10.1007/s00424-016-1903-9
Protein composition of cornified cell envelopes of epidermal keratinocytes.
Steven A C,Steinert P M
Journal of cell science
Terminally differentiated mammalian epidermal cells are lined with a 15 nm thick layer of proteins cross-linked by isodipeptide and disulfide bonds, called the cornified cell envelope (CE). A number of proteins, including involucrin, loricrin, cystatin A, filaggrin, a cysteine-rich protein (CRP) and the 'small proline-rich' proteins (SPRRs) have been reported to be components of this complex, but little information has been obtained as to their relative abundances because the acute insolubility of the CEs has precluded direct methods of analysis. To address this question, we have determined the amino acid compositions of isolated CEs, and then modelled them in terms of linear combinations of the candidate proteins. The results show that stratum corneum CEs have a loricrin content of 65-70% (w/w) in human, and 80-85% in mouse. In human epidermal CEs, the secondary contributors are filaggrin and CRP (each approximately 10%), with smaller amounts of involucrin, SPRR and cystatin A (2-5% each) also present. Mouse epidermal CEs have about the same amount of filaggrin and somewhat more SPRR, but only trace amounts of the other proteins. In marked contrast, the major constituents of the CEs of cultured keratinocytes induced to terminal differentiation in vitro are cystatin A, involucrin and CRP (each approximately 30%). No significant amount of loricrin was detected except in sloughed mouse cells, which represent a more advanced state of terminal differentiation than attached cells.(ABSTRACT TRUNCATED AT 250 WORDS)