RESUMEN
INTRODUCTION: Diesel particulate matter (DPM) emitted from diesel engines is a major source of air pollutants. DPM is composed of elemental carbon, which adsorbs organic compounds including toxic polycyclic aromatic hydrocarbons (PAHs). The skin, as well as airways, is directly exposed to DPM, and association of atopic dermatitis, psoriasis flares, and premature skin aging with air pollutant levels has been documented. In skin, the permeation of DPM and DPM-adsorbed compounds is primarily blocked by the epidermal permeability barrier deployed in the stratum corneum. Depending upon the integrity of this barrier, certain amounts of DPM and DPM-adsorbed compounds can permeate into the skin. However, this permeation into human skin has not been completely elucidated. METHODS: We assessed the permeation of PAHs (adsorbed to DPM) into skin using ex vivo normal (barrier-competent) organ-cultured human skin after application of DPM. Two major PAHs, 2-methylnaphthalene and triphenylene, and a carcinogenic PAH, benzo(a)pyrene, all found in DPM, were measured in the epidermis and dermis using liquid chromatography electrospray ionization tandem mass spectrometry. In addition, we investigated whether a topical formulation can attenuate the permeation of DPM into skin. RESULTS: 2-Methylnaphthalene, triphenylene, and benzo(a)pyrene were recovered from the epidermis. Although these PAHs were also detected in the dermis after DPM application, these PAH levels were significantly lower than those found in the epidermis. We also demonstrated that a topical formulation that has the ability to form more uniform membrane structures can significantly suppress the permeation of PAHs adsorbed to DPM into the skin. CONCLUSION: Toxic compounds adsorbed by DPM can permeate even barrier-competent skin. Hence, barrier-compromised skin, such as in atopic dermatitis, psoriasis, and xerosis, is even more vulnerable to air pollutants. A properly formulated topical mixture that forms certain membrane structures on the skin surface can effectively prevent permeation of exogenous substances, including DPM, into skin.
RESUMEN
Two serious health conditions, obesity and atopic dermatitis (AD), share some pathological features such as insulin resistance, leptin resistance and inflammation, and a growing body of evidence suggests a link between obesity and AD. Obesity predisposes an individual to and/or worsens AD, whereas AD increases the risk of obesity. Obesity and AD's interactions are mediated by cytokines, chemokines and immune cells. Obese individuals with AD are more resistant to anti-inflammatory therapy, while weight loss can alleviate AD. In this review, we summarize the evidence linking AD and obesity. We also discuss the pathogenic role of obesity in AD, and vice versa. Because of the connection between these two conditions, mitigation of one could possibly prevent the development of or alleviate the other condition. Effective management of AD and weight loss can enhance the wellness of individuals with both of these conditions. However, proper clinical studies are warranted to validate this speculation.
Asunto(s)
Dermatitis Atópica , Humanos , Obesidad/complicaciones , Inflamación/complicacionesRESUMEN
Epidermal function is regulated by numerous exogenous and endogenous factors, including age, psychological stress, certain skin disorders, ultraviolet irradiation and pollution, and epidermal function itself can regulate cutaneous and extracutaneous functions. The biophysical properties of the stratum corneum reflect the status of both epidermal function and systemic conditions. Type 2 diabetes in both murine models and humans displays alterations in epidermal functions, including reduced levels of stratum corneum hydration and increased epidermal permeability as well as delayed permeability barrier recovery, which can all provoke and exacerbate cutaneous inflammation. Because inflammation plays a pathogenic role in type 2 diabetes, a therapy that improves epidermal functions could be an alternative approach to mitigating type 2 diabetes and its associated cutaneous disorders.
Asunto(s)
Diabetes Mellitus Tipo 2 , Animales , Epidermis/patología , Epidermis/efectos de la radiación , Humanos , Inflamación/patología , Ratones , Permeabilidad , PielRESUMEN
Cetacean skin continues to be the investigative focus of researchers from several different scientific disciplines. Yet, most research on the basic functions of lipo-keratinocytes, which constitute most of the cetacean epidermis, providing the first layer of protection against various environmental aggressors (including an ever-increasing level of pollutants), is restricted to specialized literature on the permeability barrier only. In this review, we have attempted to bring together much of the recent research on the functional biology of cetacean skin, including special adaptations at the cellular, genetic and molecular level. We have correlated these data with the cetacean permeability barrier's unique structural and metabolic adaptations to fully aquatic life, including the development of secondary barriers to ward off challenges such as biofouling as well as exposure to extreme cold for the epidermis, which is outside of the insulation provided by blubber. An apparent contradiction exists between some of the reported gene loss for lipogenic enzymes in cetacean skin and the high degree of cetacean epidermal lipogenesis, as well as loss of desmocollin 1 and desmoplakin genes [while immunolocalization of these proteins is reported (Journal of Anatomy, 234, 201)] warrants a re-evaluation of the gene loss data.
Asunto(s)
Adaptación Fisiológica , Epidermis , Animales , PermeabilidadRESUMEN
Nitric oxide (NO), a signaling molecule, regulates biological functions in multiple organs/tissues, including the epidermis, where it impacts permeability barrier homeostasis, wound healing, and antimicrobial defense. In addition, NO participates in cutaneous inflammation, where it exhibits pro-inflammatory properties via the cyclooxygenase/prostaglandin pathway, migration of inflammatory cells, and cytokine production. Yet, NO can also inhibit cutaneous inflammation through inhibition of T cell proliferation and leukocyte migration/infiltration, enhancement of T cell apoptosis, as well as through down-regulation of cytokine production. Topical applications of NO-releasing products can alleviate atopic dermatitis in humans and in murine disease models. The underlying mechanisms of these discrepant effects of NO on cutaneous inflammation remain unknown. In this review, we briefly review the regulatory role of NO in cutaneous inflammation and its potential, underlying mechanisms.
Asunto(s)
Dermatitis Atópica , Óxido Nítrico , Animales , Citocinas/metabolismo , Dermatitis Atópica/metabolismo , Epidermis/metabolismo , Humanos , Inflamación/metabolismo , Ratones , Óxido Nítrico/metabolismoRESUMEN
Nitric oxide (NO), a free radical molecule synthesized by nitric oxide synthases (NOS), regulates multiple cellular functions in a variety of cell types. These NOS, including endothelial NOS (eNOS), inducible NOS (iNOS) and neural NOS (nNOS), are expressed in keratinocytes. Expression levels of both iNOS and nNOS decrease with ageing, and insufficient NO has been linked to the development of a number of disorders such as diabetes and hypertension, and to the severity of atherosclerosis. Conversely, excessive NO levels can induce cellular oxidative stress, but physiological levels of NO are required to maintain the normal functioning of cells, including keratinocytes. NO also regulates cutaneous functions, including epidermal permeability barrier homeostasis and wound healing, through its stimulation of keratinocyte proliferation, differentiation and lipid metabolism. Topical applications of a diverse group of agents which generate nitric oxide (called NO donors) such as S-nitroso-N-acetyl-D,L-penicillamine (SNAP) can delay permeability barrier recovery in barrier-disrupted skin, but iNOS is still required for epidermal permeability barrier homeostasis. This review summarizes the regulatory role that NO plays in epidermal permeability barrier functions and the underlying mechanisms involved.
Asunto(s)
Epidermis , Óxido Nítrico , Epidermis/metabolismo , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , PermeabilidadRESUMEN
BACKGROUND: Autism, a childhood behavioral disorder, belongs to a large suite of diseases, collectively referred to as autism spectrum disorders (ASD). Though multifactorial in etiology, approximately 10% of ASD are associated with atopic dermatitis (AD). Moreover, ASD prevalence increases further as AD severity worsens, though these disorders share no common causative mutations. We assessed here the link between these two disorders in the standard, valproic acid mouse model of ASD. In prior studies, there was no evidence of skin involvement, but we hypothesized that cutaneous involvement could be detected in experiments conducted in BALB/c mice. BALB/c is an albino, laboratory-bred strain of the house mouse and is among the most widely used inbred strains used in animal experimentation. METHODS: We performed our studies in valproic acid (VPA)-treated BALB/c hairless mice, a standard mouse model of ASD. Mid-trimester pregnant mice received a single intraperitoneal injection of either valproic acid sodium salt dissolved in saline or saline alone on embryonic day 12.5 and were housed individually until postnatal day 21. Only the brain and epidermis appeared to be affected, while other tissues remain unchanged. At various postnatal time points, brain, skin and blood samples were obtained for histology and for quantitation of tissue sphingolipid content and cytokine levels. RESULTS: AD-like changes in ceramide content occurred by day one postpartum in both VPA-treated mouse skin and brain. The temporal co-emergence of AD and ASD, and the AD phenotype-dependent increase in ASD prevalence correlated with early appearance of cytokine markers (i.e., interleukin [IL]-4, 5, and 13), as well as mast cells in skin and brain. The high levels of interferon (IFN)γ not only in skin, but also in brain likely account for a significant decline in esterified very-long-chain N-acyl fatty acids in brain ceramides, again mimicking known IFNγ-induced changes in AD. CONCLUSION: Baseline involvement of both AD and ASD could reflect concurrent neuro- and epidermal toxicity, possibly because both epidermis and neural tissues originate from the embryonic neuroectoderm. These studies illuminate the shared susceptibility of the brain and epidermis to a known neurotoxin, suggesting that the atopic diathesis could be extended to include ASD.
Asunto(s)
Trastorno Autístico/inducido químicamente , Trastorno Autístico/metabolismo , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/metabolismo , Fenotipo , Ácido Valproico/toxicidad , Animales , Anticonvulsivantes/toxicidad , Trastorno Autístico/genética , Dermatitis Atópica/genética , Femenino , Mediadores de Inflamación/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos BALB C , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismoRESUMEN
Loss-of-function mutations in arachidonate lipoxygenase 12B (ALOX12B) are an important cause of autosomal recessive congenital ichthyosis (ARCI). 12R-lipoxygenase (12R-LOX), the protein product of ALOX12B, has been proposed to covalently bind the corneocyte lipid envelope (CLE) to the proteinaceous corneocyte envelope, thereby providing a scaffold for the assembly of barrier-providing, mature lipid lamellae. To test this hypothesis, an in-depth ultrastructural examination of CLEs was performed in ALOX12B-/- human and Alox12b-/- mouse epidermis, extracting samples with pyridine to distinguish covalently attached CLEs from unbound (ie, noncovalently bound) CLEs. ALOX12B--/- stratum corneum contained abundant pyridine-extractable (ie, unbound) CLEs, compared with normal stratum corneum. These unbound CLEs were associated with defective post-secretory lipid processing, and were specific to 12R-LOX deficiency, because they were not observed with deficiency of the related ARCI-associated proteins, patatin-like phospholipase 1 (Pnpla1) or abhydrolase domain containing 5 (Abhd5). These results suggest that 12R-LOX contributes specifically to CLE-corneocyte envelope cross-linking, which appears to be a prerequisite for post-secretory lipid processing, and provide insights into the pathogenesis of 12R-LOX deficiency in this subtype of ARCI, as well as other conditions that display a defective CLE.
Asunto(s)
Araquidonato 12-Lipooxigenasa/genética , Ictiosis/diagnóstico por imagen , Metabolismo de los Lípidos , Proteínas/metabolismo , Animales , Araquidonato 12-Lipooxigenasa/deficiencia , Araquidonato 12-Lipooxigenasa/metabolismo , Epidermis/ultraestructura , Femenino , Humanos , Queratinocitos/ultraestructura , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Mutación , Piridinas/metabolismo , Piel/ultraestructuraRESUMEN
Diverse inherited and acquired abnormalities in epidermal structural and enzymatic proteins compromise permeability, barrier function and antimicrobial defense in atopic dermatitis (AD). Though several mutations in filaggrin (FLG) predominate, alterations in other S-100, cornified envelope precursor proteins (hornerin [HRNR], filaggrin 2 [FLG2], SPRR3, mattrin) which regulate lamellar body formation; SPINK5, which encodes the serine protease inhibitor, LEKTI1, and a fatty acid transporter, FATP4, are all separately associated with an AD phenotype. Exogenous and endogenous stressors, such as prolonged psychological stress, a low environmental humidity, or exposure to basic soaps and surfactants can further compromise barrier function and are often required to trigger disease. In the immunologists' view, the barrier abnormality is relevant only because it allows antigen and pathogen access, while stimulating Th2 cytokine production. These proteins in turn downregulate lipid synthetic enzyme and antimicrobial peptide levels, as well as multiple epidermal structural proteins, including filaggrin. Each inherited and acquired abnormality can independently compromise lamellar body secretion production, resulting in defective lamellar membrane organization and antimicrobial defense. Furthermore, elevated pH of the SC is critical for AD pathogenesis, compromising post-secretory lipid processing, while also enhancing inflammation. There are various therapeutic options that interdict different stages in this pathogenic paradigm.
Asunto(s)
Dermatitis Atópica , Eccema , Epidermis , Proteínas Filagrina , Humanos , Inflamación , FenotipoRESUMEN
Atopic dermatitis (AD) is a multifactorial, heterogeneous disease associated with epidermal barrier disruption and intense systemic inflammation. Previously, we showed that exosomes derived from human adipose tissue-derived mesenchymal stem cells (ASC-exosomes) attenuate AD-like symptoms by reducing multiple inflammatory cytokine levels. Here, we investigated ASC-exosomes' effects on skin barrier restoration by analyzing protein and lipid contents. We found that subcutaneous injection of ASC-exosomes in an oxazolone-induced dermatitis model remarkably reduced trans-epidermal water loss, while enhancing stratum corneum (SC) hydration and markedly decreasing the levels of inflammatory cytokines such as IL-4, IL-5, IL-13, TNF-α, IFN-γ, IL-17, and TSLP, all in a dose-dependent manner. Interestingly, ASC-exosomes induced the production of ceramides and dihydroceramides. Electron microscopic analysis revealed enhanced epidermal lamellar bodies and formation of lamellar layer at the interface of the SC and stratum granulosum with ASC-exosomes treatment. Deep RNA sequencing analysis of skin lesions demonstrated that ASC-exosomes restores the expression of genes involved in skin barrier, lipid metabolism, cell cycle, and inflammatory response in the diseased area. Collectively, our results suggest that ASC-exosomes effectively restore epidermal barrier functions in AD by facilitating the de novo synthesis of ceramides, resulting in a promising cell-free therapeutic option for treating AD.
Asunto(s)
Tejido Adiposo/metabolismo , Ceramidas/biosíntesis , Dermatitis Atópica/tratamiento farmacológico , Epidermis/metabolismo , Exosomas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Animales , Ceramidas/metabolismo , Dermatitis Atópica/patología , Femenino , Humanos , RatonesRESUMEN
Pigmentation evolved in ancestral humans to protect against toxic, ultraviolet B irradiation, but the question remains: "what is being protected?" Because humans with dark pigmentation display a suite of superior epidermal functions in comparison with their more lightly pigmented counterparts, we hypothesized and provided evidence that dark pigmentation evolved in Africa to support cutaneous function. Because our prior clinical studies also showed that a restoration of a competent barrier dampens cutaneous inflammation, we hypothesized that resistance to inflammation could have provided pigmented hominins with yet another, important evolutionary benefit. We addressed this issue here in two closely related strains of hairless mice, endowed with either moderate (Skh2/J) or absent (Skh1) pigmentation. In these models, we showed that (a) pigmented mice display a markedly reduced propensity to develop inflammation after challenges with either a topical irritant or allergen in comparison with their nonpigmented counterparts; (b) visible and histologic evidence of inflammation was paralleled by reduced levels of pro-inflammatory cytokines (i.e., IL-1α and INFα); (c) because depigmentation of Skh2/J mouse skin enhanced both visible inflammation and pro-inflammatory cytokine levels after comparable pro-inflammatory challenges, the reduced propensity to develop inflammation was directly linked to the presence of pigmentation; and (d) furthermore, in accordance with our prior work showing that pigment production endows benefits by reducing the surface pH of skin, acidification of albino (Skh1) mouse skin also protected against inflammation, and equalized cytokine levels to those found in pigmented skin. In summary, pigmentation yields a reduced propensity to develop inflammation, consistent with our hypothesis that dark pigmentation evolved in ancestral humans to provide a suite of barrier-linked benefits that now include resistance to inflammation.
RESUMEN
The corneocyte lipid envelope (CLE), a monolayer of ω-hydroxyceramides whose function(s) remain(s) uncertain, is absent in patients with autosomal recessive congenital ichthyoses with mutations in enzymes that regulate epidermal lipid synthesis. Secreted lipids fail to transform into lamellar membranes in certain autosomal recessive congenital ichthyosis epidermis, suggesting the CLE provides a scaffold for the extracellular lamellae. However, because cornified envelopes are attenuated in these autosomal recessive congenital ichthyoses, the CLE may also provide a scaffold for subjacent cornified envelope formation, evidenced by restoration of cornified envelopes after CLE rescue. We provide multiple lines of evidence that the CLE originates as lamellar body-limiting membranes fuse with the plasma membrane: (i) ABCA12 patients and Abca12-/- mice display normal CLEs; (ii) CLEs are normal in Netherton syndrome, despite destruction of secreted LB contents; (iii) CLEs are absent in VSP33B-negative patients; (iv) limiting membranes of lamellar bodies are defective in lipid-synthetic autosomal recessive congenital ichthyoses; and (v) lipoxygenases, lipase activity, and LIPN co-localize within putative lamellar bodies.
Asunto(s)
ADN/genética , Eritrodermia Ictiosiforme Congénita/genética , Metabolismo de los Lípidos/genética , Lípidos/genética , Mutación , Piel/metabolismo , Animales , Análisis Mutacional de ADN , Humanos , Eritrodermia Ictiosiforme Congénita/metabolismo , Eritrodermia Ictiosiforme Congénita/patología , Piel/patologíaRESUMEN
We compare here the principal characteristics of over-the-counter moisturizers with physiologic lipid-based barrier repair therapy. Moisturizers are standard ancillary therapy for anti-inflammatory skin disorders, like atopic dermatitis (AD), and can attenuate the emergence of AD, the initial step in the "atopic march." But not all moisturizers are beneficial; some can make skin function worse, and can even induce inflammation, possibly accounting for the frequent occurrence of "sensitive skin" in women. In contrast, physiologic lipid-based barrier repair therapy, if comprised of the 3 key stratum corneum lipids, in sufficient quantities and at an appropriate molar ratio, can correct the barrier abnormality and reduce inflammation in AD, and perhaps in other inflammatory dermatoses.
Asunto(s)
Ceramidas/administración & dosificación , Dermatitis Atópica/tratamiento farmacológico , Manejo de la Enfermedad , Emolientes/administración & dosificación , Pérdida Insensible de Agua/efectos de los fármacos , Animales , Ceramidas/metabolismo , Dermatitis Atópica/metabolismo , Emolientes/metabolismo , Humanos , Lípidos/administración & dosificación , Piel/efectos de los fármacos , Piel/metabolismo , Crema para la Piel/administración & dosificación , Crema para la Piel/metabolismo , Pérdida Insensible de Agua/fisiologíaRESUMEN
Mutations in several lipid synthetic enzymes that block fatty acid and ceramide production produce autosomal recessive congenital ichthyoses (ARCIs) and associated abnormalities in permeability barrier homeostasis. However, the basis for the phenotype in patients with NIPAL4 (ichthyin) mutations (among the most prevalent ARCIs) remains unknown. Barrier function was abnormal in an index patient and in canines with homozygous NIPAL4 mutations, attributable to extensive membrane stripping, likely from detergent effects of nonesterified free fatty acid. Cytotoxicity compromised not only lamellar body secretion but also formation of the corneocyte lipid envelope (CLE) and attenuation of the cornified envelope (CE), consistent with a previously unrecognized, scaffold function of the CLE. Together, these abnormalities result in failure to form normal lamellar bilayers, accounting for the permeability barrier abnormality and clinical phenotype in NIPA-like domain-containing 4 (NIPAL4) deficiency. Thus, NIPAL4 deficiency represents another lipid synthetic ARCI that converges on the CLE (and CE), compromising their putative scaffold function. However, the clinical phenotype only partially improved after normalization of CLE and CE structure with topical ω-O-acylceramide because of ongoing accumulation of toxic metabolites, further evidence that proximal, cytotoxic metabolites contribute to disease pathogenesis.
Asunto(s)
Modelos Animales de Enfermedad , Epidermis/patología , Ictiosis/patología , Lípidos/análisis , Mutación , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genética , Adulto , Animales , Perros , Epidermis/metabolismo , Femenino , Homocigoto , Humanos , Ictiosis/genética , Ictiosis/metabolismo , Masculino , Linaje , FenotipoRESUMEN
I review how diverse inherited and acquired abnormalities in epidermal structural and enzymatic proteins converge to produce defective permeability barrier function and antimicrobial defense in patients with atopic dermatitis (AD). Although best known are mutations in filaggrin (FLG), mutations in other member of the fused S-100 family of proteins (ie, hornerin [hrn] and filaggrin 2 [flg-2]); the cornified envelope precursor (ie, SPRR3); mattrin, which is encoded by TMEM79 and regulates the assembly of lamellar bodies; SPINK5, which encodes the serine protease inhibitor lymphoepithelial Kazal-type trypsin inhibitor type 1; and the fatty acid transporter fatty acid transport protein 4 have all been linked to AD. Yet these abnormalities often only predispose to AD; additional acquired stressors that further compromise barrier function, such as psychological stress, low ambient humidity, or high-pH surfactants, often are required to trigger disease. T(H)2 cytokines can also compromise barrier function by downregulating expression of multiple epidermal structural proteins, lipid synthetic enzymes, and antimicrobial peptides. All of these inherited and acquired abnormalities converge on the lamellar body secretory system, producing abnormalities in lipid composition, secretion, and/or extracellular lamellar membrane organization, as well as antimicrobial defense. Finally, I briefly review therapeutic options that address this new pathogenic paradigm.
Asunto(s)
Dermatitis Atópica/fisiopatología , Proteínas de Transporte de Ácidos Grasos/metabolismo , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Inhibidoras de Proteinasas Secretoras/metabolismo , Piel/patología , Animales , Secreciones Corporales/fisiología , Dermatitis Atópica/etiología , Proteínas de Transporte de Ácidos Grasos/genética , Proteínas Filagrina , Interacción Gen-Ambiente , Humanos , Inmunidad Innata , Cuerpos de Inclusión/genética , Cuerpos de Inclusión/inmunología , Proteínas de Filamentos Intermediarios/genética , Metabolismo de los Lípidos/genética , Proteínas de la Membrana/genética , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Proteolisis , Inhibidor de Serinpeptidasas Tipo Kazal-5RESUMEN
Humans with darkly pigmented skin display superior permeability barrier function in comparison with humans with lightly pigmented skin. The reduced pH of the stratum corneum (SC) of darkly pigmented skin could account for enhanced function, because acidifying lightly pigmented human SC resets barrier function to darkly pigmented levels. In SKH1 (nonpigmented) versus SKH2/J (pigmented) hairless mice, we evaluated how a pigment-dependent reduction in pH could influence epidermal barrier function. Permeability barrier homeostasis is enhanced in SKH2/J versus SKH1 mice, correlating with a reduced pH in the lower SC that colocalizes with the extrusion of melanin granules. Darkly pigmented human epidermis also shows substantial melanin extrusion in the outer epidermis. Both acute barrier disruption and topical basic pH challenges accelerate reacidification of SKH2/J (but not SKH1) SC, while inducing melanin extrusion. SKH2/J mice also display enhanced expression of the SC acidifying enzyme, secretory phospholipase A2f (sPLA2f). Enhanced barrier function of SKH2/J mice could be attributed to enhanced activity of two acidic pH-dependent, ceramide-generating enzymes, ß-glucocerebrosidase and acidic sphingomyelinase, leading to accelerated maturation of SC lamellar bilayers. Finally, organotypic cultures of darkly pigmented human keratinocytes display enhanced barrier function in comparison with lightly pigmented cultures. Together, these results suggest that the superior barrier function of pigmented epidermis can be largely attributed to the pH-lowering impact of melanin persistence/extrusion and enhanced sPLA2f expression.
Asunto(s)
Ácidos/metabolismo , Epidermis/metabolismo , Fosfolipasas A2 Grupo II/metabolismo , Homeostasis/genética , Melanocitos/metabolismo , Pigmentación de la Piel/fisiología , Animales , Ceramidas/biosíntesis , Gránulos Citoplasmáticos/metabolismo , Gránulos Citoplasmáticos/ultraestructura , Células Epidérmicas , Femenino , Glucosilceramidasa/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Queratinocitos/metabolismo , Membrana Dobles de Lípidos/metabolismo , Masculino , Melaninas/metabolismo , Melanocitos/ultraestructura , Ratones Pelados , Microscopía Electrónica , Técnicas de Cultivo de Órganos , Comunicación Paracrina/fisiología , Permeabilidad , Esfingomielina Fosfodiesterasa/metabolismoRESUMEN
Corneocytes in mammalian stratum corneum are surrounded by a monolayer of covalently bound ω-OH-ceramides that form the corneocyte (-bound) lipid envelope (CLE). We review here the structure, composition, and possible functions of this structure, with insights provided by inherited and acquired disorders of lipid metabolism. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.
Asunto(s)
Epidermis/metabolismo , Metabolismo de los Lípidos/fisiología , Lípidos , Animales , Células Epidérmicas , HumanosRESUMEN
Excessive Th2 cell signaling and IgE production play key roles in the pathogenesis of atopic dermatitis (AD). Yet, recent information suggests that the inflammation in AD instead is initiated by inherited insults to the barrier, including a strong association between mutations in FILAGGRIN and SPINK5 in Netherton syndrome, the latter of which provides an important clue that AD is provoked by excess serine protease activity. But acquired stressors to the barrier may also be required to initiate inflammation in AD, and in addition, microbial colonization by Staphylococcus aureus both amplifies inflammation, but also further stresses the barrier in AD. Therapeutic implications of these insights are as follows: While current therapy has been largely directed toward ameliorating Th2-mediated inflammation and/or pruritus, these therapies are fraught with short-term and potential long-term risks. In contrast, "barrier repair" therapy, with a ceramide-dominant triple-lipid mixture of stratum corneum lipids, is more logical, of proven efficacy, and it provides a far-improved safety profile.