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1.
Matrix Biol ; 110: 91-105, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35504439

RESUMO

Epidermolysis bullosa (EB), a phenotypically and genetically heterogeneous disorder, has been linked to mutations in the genes encoding structural proteins that reinforce skin integrity via dermal-epidermal adhesion. Breakdowns in these adhesion mechanisms result in four different subtypes of EB classified on the basis of the level of tissue separation within the cutaneous basement membrane zone (BMZ). Mutations in as many as 17 distinct genes that encode structural proteins in the BMZ have been linked to EB. Despite the clinical and histopathological confirmation of EB, many cases remain genetically unsolved. Technical advancements in next-generation sequencing have paved the way for the identification of genes involved in the pathophysiology of EB. Structural proteins have long been identified as the candidate molecules altered in EB, however, recently non-structural proteins, encoded for example by PLOD3, USB1, EXPH5, and KLHL24, involved in enzymatic modification or migration of structural proteins have been implicated. In this overview, we discuss recent work regarding these proteins vis-à-vis their function, associated clinical manifestations, and involvement in the pathogenesis of EB.


Assuntos
Epidermólise Bolhosa , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Membrana Basal/metabolismo , Epiderme/patologia , Epidermólise Bolhosa/metabolismo , Humanos , Mutação , Diester Fosfórico Hidrolases/genética , Pele/metabolismo
2.
J Fish Dis ; 45(7): 971-974, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35475494

RESUMO

A wild caught white catfish (Ameiurus catus Linnaeus) developed multiple cutaneous masses. Cytology revealed neoplastic lymphocytes and microscopy confirmed dermal infiltration with epitheliotropism in the epidermis, oral mucosa, and cornea, without internal organ involvement. Transmission electron microscopy did not identify viral particles. Histopathology supported cutaneous epitheliotropic lymphosarcoma, a condition most commonly reported in mammals. This is the first reported case of cutaneous epitheliotropic lymphosarcoma in an ictalurid and one of the few published cases of this condition in any fish species.


Assuntos
Doenças dos Peixes , Ictaluridae , Linfoma não Hodgkin , Neoplasias Cutâneas , Animais , Epiderme/patologia , Mamíferos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/veterinária
3.
Front Immunol ; 13: 817040, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35401573

RESUMO

Microabscess of neutrophils in epidermis is one of the histological hallmarks of psoriasis. The axis of neutrophil-keratinocyte has been thought to play a critical role in the pathogenesis of psoriasis. However, the features and mechanism of interaction between the two cell types remain largely unknown. Herein, we found that blood neutrophils were increased in psoriasis patients, positively correlated with disease severity and highly expressed CD66b, but not CD11b and CD62L compared to healthy controls. Keratinocytes expressed high levels of psoriasis-related inflammatory mediators by direct and indirect interaction with neutrophils isolated from psoriasis patients and healthy controls. The capacity of neutrophils in provoking keratinocytes inflammatory response was comparable between the two groups and is dependent on IL-17A produced by itself. Neutrophils isolated from psoriasis patients displayed more transcriptome changes related to integrin and increased migration capacity toward keratinocytes with high CD11b expression on cell surface. Of interest, neutrophils were more susceptible to keratinocyte stimulation than to fibroblasts and human umbilical vein endothelial cells (HUVECs) in terms of CD11b expression and the production of ROS and NETs. In conclusion, neutrophils from psoriasis patients gain a strong capacity of IL-17A production and integrins expression that possibly facilitates their abilities to promote production of psoriasis-related inflammatory mediators and migration, a phenomenon likely induced by their interaction with keratinocytes but not with fibroblasts. These findings provide a proof-of-concept that development of new drugs targeting migration of neutrophils could be a more specific and safe solution to treat psoriasis.


Assuntos
Neutrófilos , Psoríase , Células Endoteliais/metabolismo , Epiderme/patologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-17/metabolismo , Queratinócitos/metabolismo , Neutrófilos/metabolismo , Psoríase/patologia
4.
Int J Dermatol ; 61(7): 872-873, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35348203

RESUMO

BACKGROUND: Leprosy is one of the main health problems in developing countries. It can show many different clinical presentations. CASE REPORT: A 37-yr-old woman with multiple reddish-brown papules on the lower and upper limbs, including the palms. The initial clinical impression was pityriasis lichenoides chronica. Biopsies were taken. The specimen from the left shin showed classical histological features of lepromatous leprosy. The specimen from the left thigh was similar to lipidized dermatofibroma showing epidermal hyperplasia with basal layer hyperpigmentation, a narrow Grenz zone, and spindle xanthomatous cells among dermal fibers. Fite-Faraco staining revealed many bacilli. DISCUSSION: No matter the clinical presentation, in the presence of lipidized macrophages, Fite-Faraco staining (an inexpensive method available worldwide) should be performed to rule out leprosy, even in nonendemic areas or associated with a tumor.


Assuntos
Histiocitoma Fibroso Benigno , Hanseníase Virchowiana , Hanseníase , Biópsia , Epiderme/patologia , Feminino , Humanos , Hanseníase/patologia , Hanseníase Virchowiana/diagnóstico , Hanseníase Virchowiana/patologia
5.
Clin Rheumatol ; 41(7): 2179-2187, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35277778

RESUMO

OBJECTIVES: Localized scleroderma (LSc) is a disease characterized by the excessive deposition of collagen and thereby thickening of the dermis. In recent years, studies reported that LSc demonstrated compromised skin barrier related to the progression of the disease. However, human studies examining epidermis in scleroderma are still sparse and lack systematic research. This study aims to investigate the structural and functional changes in the LSc epidermis and further explore the underlying mechanisms, providing a new angle to treat LSc in the clinic. METHODS: A total of 136 skin sites, including lesion and non-lesion control, from 27 LSc patients were analyzed. Ultrasonic testing, trans-epidermal water loss (TEWL), and epidermal hydration were assessed to investigate the structural and functional alternations; correlations between these parameters were analyzed. To explore the underlying mechanism, skin-fibrosis mouse model and cellular model by bleomycin (BLM) were deployed. RESULTS: The epidermal thickness was markedly increased, with a significant decline of hydration (dryness) in the LSc lesion skin. Epidermal hydration presented a negative correlation with the thickness. TEWL was not altered. The mouse model validated these morphological changes in the epidermis and indicated that interleukin-6 (IL-6) was significantly elevated. Furthermore, cellular study demonstrated that increased phosphorylation of p38 in keratinocyte promoted the secretion of IL-6, stimulating cell proliferation. CONCLUSION: This study characterized the epidermal alterations in LSc patients, suggesting that keratinocyte-derived abnormal IL-6 secretion can lead to the thickening of the epidermis, promoting dryness. The topical application of moisturizer may largely relieve dryness and related pruritus, thus improve the quality of life in LSc patients. Key Points • Epidermal thickness was increased in LSc lesion skin with declined hydration level. • Skin fibrosis mouse model validated the epidermal alteration in LSc patient. • p38-dependent IL-6 overexpression in keratinocyte result in epidermal thickening.


Assuntos
Epiderme , Interleucina-6 , Esclerodermia Localizada , Animais , Epiderme/metabolismo , Epiderme/patologia , Fibrose , Humanos , Interleucina-6/genética , Camundongos , Qualidade de Vida , Esclerodermia Localizada/patologia , Pele/patologia
6.
Ultrastruct Pathol ; 46(2): 217-235, 2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-35243959

RESUMO

Vitiligo is an idiopathic acquired chronic stigmatizing disease. It is a pigmentary disorder that affects the skin and the mucous membranes, and it is characterized by well-circumscribed, depigmented milky white macules and patches. It has an estimated prevalence of 0.5-2% of the population worldwide. In the previous studies, several mechanisms such as autoimmune, oxidative stress, genetic factors, melanocytorrhagy, and neural hypothesis have been suggested for vitiligo pathogenesis.We aimed to assess the morphological changes of epidermal melanocytes and keratinocytes in patients with vitiligo. This aim will be fulfilled by histological, ultrastructural, and immunohistochemical analysis of skin biopsies from lesioned and non-lesioned sites in vitiligo patients.The study was carried out on 15 selected patients with stable vitiligo vulgaris but not receiving treatment in the last year and they fulfilled our inclusion criteria.Biopsies were taken from lesioned and non-lesioned sites in the same vitiligo patients, and they are processed for examinations by LM (using Hx & E, and Masson Fontana stain), immunohistochemical analysis (using Melan-A, E-cadherin, and caspase-3), and TEM (to demonstrate the ultra-structures).By LM, staining with Hx & E, lesioned skin in vitiligo patients showed hyperkeratosis, basal vacuolization, acanthosis with an increase in the epidermal thickness, ballooning of keratinocytes, and spongiosis. Regarding melanocytes, we observed a few numbers of melanocytes, also we detected some basal epidermal cells contain brown melanin granules. Using Fontana-Masson stain, we found that the melanin pigment is present in both lesioned and non-lesioned skin of vitiligo patients. We confirmed the presence of melanocytes in the lesioned skin by the immunohistochemical staining with Melan-A. The epidermal cells in lesioned skin of vitiligo patients showed weak positive expression of E-cadherin between them and an increase in the number of apoptotic Caspase-3 positive cells. BY TEM, the lesioned skin in vitiligo patients showed that the keratinocytes and melanocytes had various degenerative changes, disturbance of desmosomes in between keratinocytes, and absence of melanosomes in the keratinocytes. The detected melanocytes were degenerated and contained some melanosomes, melanin granules, and autophagosomes.We concluded that vitiligo pathogenesis is a combination of several factors and cannot be explained by only one mechanism. The pathology in the lesioned vitiliginous skin is a combination of several degenerative changes in keratinocytes, and melanocytes.


Assuntos
Vitiligo , Epiderme/metabolismo , Epiderme/patologia , Humanos , Queratinócitos , Melanócitos/ultraestrutura , Pele , Vitiligo/patologia
7.
Biotechniques ; 72(5): 194-200, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35289681

RESUMO

Human skin equivalents (HSEs) are in vitro models of human skin. They are used to study skin development, diseases, wound healing and toxicity. The gold standard of analysis is histological sectioning, which both limits three-dimensional assessment of the tissue and prevents live culture monitoring. Optical coherence tomography (OCT) has previously been used to visualize in vivo human skin and in vitro models. OCT is noninvasive and enables real-time volumetric analysis of HSEs. The techniques presented here demonstrate the use of OCT imaging to track HSE epidermal thickness over 8 weeks of culture and improve upon previous processing of OCT images by presenting algorithms that automatically quantify epidermal thickness. Through volumetric automated analysis, HSE morphology can be accurately tracked in real time.


Assuntos
Epiderme , Tomografia de Coerência Óptica , Algoritmos , Epiderme/anatomia & histologia , Epiderme/patologia , Humanos , Pele/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Cicatrização
8.
Neurobiol Aging ; 113: 108-117, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35325812

RESUMO

Aged and photoaged skin exhibit fine wrinkles that are signs of epidermal inflammation and degeneration. It has been shown that healthy elderly skin expresses amyloidogenic proteins, including α-Synuclein, which are known to oligomerize and trigger inflammation and neurodegeneration. However, little is known about their putative role in skin physiology and sensitivity. To unravel this possible role, we investigated the impact of oligomeric α-Synuclein (Oα-Syn) in 2D and 3D keratinocyte human models. Exogenous Oα-Syn caused degeneration of reconstructed human epidermis (RHE) by diminishing proliferation and thickness of the stratum basale. Oα-Syn also increased NF-kB nuclear translocation in keratinocytes and triggered inflammation in the RHE, by increasing expression of interleukin-1ß and tumor necrosis factor-alpha, and the release of tumor necrosis factor-alpha in a time-dependent manner. Dexamethasone and an IL-1ß inhibitor partially diminished RHE degeneration caused by Oα-Syn. These findings suggest that Oα-Syn induces epidermal inflammation and decreases keratinocyte proliferation, and therefore might contribute to epidermal degeneration observed in human skin aging.


Assuntos
Fator de Necrose Tumoral alfa , alfa-Sinucleína , Idoso , Epiderme/metabolismo , Epiderme/patologia , Humanos , Inflamação/metabolismo , Queratinócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , alfa-Sinucleína/metabolismo
9.
An Bras Dermatol ; 97(3): 399-400, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35321801

RESUMO

A 34-year-old female was referred to our department, complaining of multiple asymptomatic lesions that appeared two weeks previously. The patient had active nephritis with nephrotic syndrome and was treated with immunosuppressive therapies. Physical examination revealed multiple well-circumscribed rounds of flat brownish plaques with slightly elevated borders, some of which were covered by scales. The number of lesions was nine in total. Skin biopsy specimens showed dyskeratotic cells in the thinned epidermis with cornoid lamella, and the absence of a granular cell layer. The development of porokeratosis was considered to be related to immunosuppressive therapy or the activity of nephritis.


Assuntos
Exantema , Nefrite , Síndrome Nefrótica , Poroceratose , Adulto , Epiderme/patologia , Feminino , Humanos , Síndrome Nefrótica/complicações , Poroceratose/complicações , Poroceratose/patologia
10.
Int J Mol Sci ; 23(4)2022 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-35216228

RESUMO

Currently, the mechanism of progression of atopic dermatitis (AD) is not well understood because there is no physiologically appropriate disease model in terms of disease complexity and multifactoriality. Type 2 inflammation, mediated by interleukin (IL)-4 and IL-13, plays an important role in AD. In this study, full-thickness human skin equivalents consisting of human-derived cells were fabricated from pumpless microfluidic chips and stimulated with IL-4 and IL-13. The morphological properties, gene expression, cytokine secretion and protein expression of the stimulated human skin equivalent (HSE) epidermis were investigated. The results showed epidermal and spongy formations similar to those observed in lesions in AD, and decreased expression of barrier-related filaggrin, loricrin and involucrin genes and proteins induced by IL-4Rα signaling. In addition, we induced the expression of carbonic anhydrase II (CAII), a gene specifically expressed in the epidermis of patients with AD. Thus, AD human skin equivalents can be used to mimic the key pathological features of atopic dermatitis, overcoming the limitations of existing studies that rely solely on mouse models and have been unable to translate their effects to humans. Our results will be useful for future research on the development of therapeutic agents for atopic dermatitis.


Assuntos
Dermatite Atópica/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Pele/metabolismo , Animais , Dermatite Atópica/tratamento farmacológico , Eczema/tratamento farmacológico , Eczema/metabolismo , Eczema/patologia , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Epiderme/patologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Dispositivos Lab-On-A-Chip , Proteínas de Membrana/farmacologia , Ratos , Pele/efeitos dos fármacos , Pele/patologia
11.
Eur J Endocrinol ; 186(4): 441-455, 2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35113805

RESUMO

BACKGROUND: Chronic wounds (e.g. diabetic foot ulcers) reduce the quality of life, yet treatments remain limited. Glucocorticoids (activated by the enzyme 11ß-hydroxysteroid dehydrogenase type 1, 11ß-HSD1) impair wound healing. OBJECTIVES: Efficacy, safety, and feasibility of 11ß-HSD1 inhibition for skin function and wound healing. DESIGN: Investigator-initiated, double-blind, randomized, placebo-controlled, parallel-group phase 2b pilot trial. METHODS: Single-center secondary care setting. Adults with type 2 diabetes mellitus without foot ulcers were administered 400 mg oral 11ß-HSD1 inhibitor AZD4017 (n = 14) or placebo (n = 14) bi-daily for 35 days. Participants underwent 3-mm full-thickness punch skin biopsies at baseline and on day 28; wound healing was monitored after 2 and 7 days. Computer-generated 1:1 randomization was pharmacy-administered. Analysis was descriptive and focused on CI estimation. Of the 36 participants screened, 28 were randomized. RESULTS: Exploratory proof-of-concept efficacy analysis suggested AZD4017 did not inhibit 24-h ex vivoskin 11ß-HSD1 activity (primary outcome; difference in percentage conversion per 24 h 1.1% (90% CI: -3.4 to 5.5) but reduced systemic 11ß-HSD1 activity by 87% (69-104%). Wound diameter was 34% (7-63%) smaller with AZD4017 at day 2, and 48% (12-85%) smaller after repeat wounding at day 30. AZD4017 improved epidermal integrity but modestly impaired barrier function. Minimal adverse events were comparable to placebo. Recruitment rate, retention, and data completeness were 2.9/month, 27/28, and 95.3%, respectively. CONCLUSION: A phase 2 trial is feasible, and preliminary proof-of-concept data suggests AZD4017 warrants further investigation in conditions of delayed healing, for example in diabetic foot ulcers. SIGNIFICANCE STATEMENT: Stress hormone activation by the enzyme 11ß-HSD type 1 impairs skin function (e.g. integrity) and delays wound healing in animal models of diabetes, but effects in human skin were previously unknown. Skin function was evaluated in response to treatment with a 11ß-HSD type 1 inhibitor (AZD4017), or placebo, in people with type 2 diabetes. Importantly, AZD4017 was safe and well tolerated. This first-in-human randomized, controlled, clinical trial found novel evidence that 11ß-HSD type 1 regulates skin function in humans, including improved wound healing, epidermal integrity, and increased water loss. Results warrant further studies in conditions of impaired wound healing, for example, diabetic foot ulcers to evaluate 11ß-HSD type 1 as a novel therapeutic target forchronic wounds.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Diabetes Mellitus Tipo 2/complicações , Pé Diabético/tratamento farmacológico , Niacinamida/análogos & derivados , Piperidinas/uso terapêutico , Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Pé Diabético/patologia , Método Duplo-Cego , Epiderme/efeitos dos fármacos , Epiderme/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/uso terapêutico , Projetos Piloto , Qualidade de Vida , Pele/patologia , Pele/fisiopatologia , Resultado do Tratamento
12.
Sci Rep ; 12(1): 795, 2022 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-35039587

RESUMO

The epidermal basement membrane deteriorates with aging. We previously reported that basement membrane reconstruction not only serves to maintain epidermal stem/progenitor cells in the epidermis, but also increases collagen fibrils in the papillary dermis. Here, we investigated the mechanism of the latter action. Collagen fibrils in the papillary dermis were increased in organotypic human skin culture treated with matrix metalloproteinase and heparinase inhibitors. The expression levels of COL5A1 and COL1A1 genes (encoding collagen type V α 1 chain and collagen type I α 1 chain, respectively) were increased in fibroblasts cultured with conditioned medium from a skin equivalent model cultured with the inhibitors and in keratinocytes cultured on laminin-511 E8 fragment-coated plates. We then examined cytokine expression, and found that the inhibitors increased the expression of PDGF-BB (platelet-derived growth factor consisting of two B subunits) in epidermis. Expression of COL5A1 and COL1A1 genes was increased in cultured fibroblasts stimulated with PDGF-BB. Further, the bifunctional inhibitor hydroxyethyl imidazolidinone (HEI) increased skin elasticity and the thickness of the papillary dermis in the skin equivalent. Taken together, our data suggests that reconstructing the basement membrane promotes secretion of PDGF-BB by epidermal keratinocytes, leading to increased collagen expression at the papillary dermis.


Assuntos
Membrana Basal/fisiologia , Epiderme/fisiologia , Colágenos Associados a Fibrilas/fisiologia , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Regeneração/fisiologia , Envelhecimento da Pele/patologia , Envelhecimento da Pele/fisiologia , Membrana Basal/metabolismo , Becaplermina/genética , Becaplermina/metabolismo , Células Cultivadas , /metabolismo , Colágeno Tipo V/genética , Colágeno Tipo V/metabolismo , Células Epidérmicas/metabolismo , Epiderme/metabolismo , Epiderme/patologia , Colágenos Associados a Fibrilas/genética , Colágenos Associados a Fibrilas/metabolismo , Expressão Gênica , Humanos , Queratinócitos/metabolismo , Metaloproteinases da Matriz/farmacologia , Regeneração/genética
13.
Biochem Biophys Res Commun ; 591: 68-75, 2022 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-34999256

RESUMO

The regulatory mechanism of hematopoiesis and innate immunity in Drosophila is highly similar to that in mammals, and Drosophila has become a suitable model to understand vertebrate hematopoiesis and the immune response. JAK-STAT signaling pathway components are widely conserved during evolution, and contribute to hematopoiesis and multiple tissue damage and immune responses. Here, we demonstrate that Stat92E is widely expressed in the lymph gland, and the loss of jumu inhibits the maintenance of the JAK/STAT pathway in the CZ and MZ but not in the PSC of the lymph gland. Furthermore, we found that clean puncture wounding of the larval epidermis can lead to the activation of JAK/STAT signaling and the generation of lamellocytes, and Jumu is required for the activation of JAK/STAT in response to epidermal wounds.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Epiderme/patologia , Janus Quinases/metabolismo , Linfangiogênese , Vasos Linfáticos/metabolismo , Fatores de Transcrição/metabolismo , Ferimentos e Lesões/metabolismo , Animais , Núcleo Celular/metabolismo , Proteínas de Drosophila/genética , Hemócitos/metabolismo , Mutação/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética
14.
J Eur Acad Dermatol Venereol ; 36(5): 726-738, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35015925

RESUMO

BACKGROUND: Ichthyoses are pathogenetically characterized by a pronounced disorder of the epidermal barrier. Clinically, hyperkeratosis, severe scaling and erythroderma are present on the entire integument. The time-consuming therapy includes daily baths and the application of skin care products to restore the epidermal barrier. OBJECTIVES AND METHODS: To enhance the knowledge about the structure and function of the epidermal barrier in ichthyoses, we conducted clinical, biophysical and electron microscopical measurements on 46 patients with ichthyoses, including autosomal recessive ichthyoses, keratinopathic ichthyoses, X-chromosomal-recessive ichthyosis and Netherton syndrome. RESULTS: The patients displayed a significantly decreased skin hydration along with unexpectedly low transepidermal waterloss values. Electron microscopical examinations demonstrated a severe occlusion of the epidermis by lipid remnants of skin care products in the stratum corneum. We found decreased intercellular lipid lamellae and an increased undulation of the corneocyte membrane of all ichthyoses, mostly pronounced in Netherton syndrome. The lipid profiles of ichthyoses showed decreased esterified Ω-hydroxy-sphingosine (EOS) ceramide levels. CONCLUSIONS: The results demonstrate the extent of the epidermal barrier disruption in ichthyoses. In combination with the knowledge about pathogenetic causes, individually improved therapeutic options can be derived from our results. In the future, the analyses of the organization of intercellular lipid lamellae and corneocyte membrane undulation will enable improved investigations of the epidermal barrier in ichthyoses and may be used to study and evaluate possible effects of topical skin preparations.


Assuntos
Ictiose Lamelar , Ictiose , Síndrome de Netherton , Ceramidas , Epiderme/patologia , Humanos , Ictiose/patologia , Microscopia Eletrônica
15.
Life Sci ; 288: 120181, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34843737

RESUMO

AIMS: Sunscreen use, which prolonged the time required to develop sunburn by reducing the irradiance (mW/cm2) of the UVB radiation, is thought to protect the skin from developing cancers. Recently, in addition to fluence (mJ/cm2), irradiance of the UVB radiation was demonstrated to play an important role leading to photocarcinogenesis of the skin. After equivalent fluence of UVB exposure, enhanced aberrant keratinocyte proliferation contributes significantly to the photocarcinogenic capacity of low irradiance (LI) UVB as compared to its high irradiance (HI) UVB counterpart. However, the mechanism involved remains unclear. MAIN METHODS: Relevant cell and animal models were employed to investigate the effects of equivalent UVB fluence administered at HI or LI on keratinocyte proliferation. Additionally, the mechanisms involved were also explored. KEY FINDINGS: We found that at equivalent fluence, LIUVB induces significantly higher reactive oxidative species (ROS) production, cell proliferation, as well as phosphorylated AKT (pAKT) expression in both cell and animal models as compare to its HIUVB counterpart. Pretreating cultured keratinocytes with antioxidant or AKT inhibitor significantly reduced the UVB-induced ROS, cell proliferation, and pAKT expression. Additionally, these pretreatments abrogate the difference between the LI and HIUVB treated keratinocytes. Similar findings were noted using animal model treated with AKT inhibitor. SIGNIFICANCE: In summary, at equivalent fluence, LIUVB induces significantly more aberrant epidermal proliferation via enhanced ROS and pAKT signaling. Reducing UVB-induced AKT phosphorylation presents a novel strategy to improve the protective capacity of the currently available sunscreens.


Assuntos
Proliferação de Células , Epiderme/patologia , Queratinócitos/patologia , Pele/patologia , Protetores Solares , Raios Ultravioleta/efeitos adversos , Animais , Ciclo Celular , Epiderme/efeitos da radiação , Queratinócitos/efeitos da radiação , Camundongos , Camundongos Pelados , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pele/efeitos da radiação
16.
J Eur Acad Dermatol Venereol ; 36(3): 462-471, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34724272

RESUMO

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory disease of the apocrine gland-rich (AGR) skin region. The initial steps of disease development are not fully understood, despite intense investigations into immune alterations in lesional HS skin. OBJECTIVES: We aimed to systematically investigate the inflammatory molecules involved in three stages of HS pathogenesis, including healthy AGR, non-lesional HS and lesional HS skin, with the parallel application of multiple mRNA and protein-based methods. METHODS: Immune cell counts (T cells, dendritic cells, macrophages), Th1/Th17-related molecules (IL-12B, TBX21, IFNG, TNFA, IL-17, IL10, IL-23A, TGFB1, RORC, CCL20), keratinocyte-related sensors (TLR2,4), mediators (S100A7, S100A8, S100A9, DEFB4B, LCN2, CAMP, CCL2) and pro-inflammatory molecules (IL1B, IL6, TNFA, IL-23A) were investigated in the three groups by RNASeq, RT-qPCR, immunohistochemistry and immunofluorescence. RESULTS: Epidermal changes were already detectable in non-lesional HS skin; the epidermal occurrence of antimicrobial peptides (AMPs), IL-1ß, TNF-α and IL-23 was highly upregulated compared with healthy AGR skin. In lesional HS epidermis, TNF-α and IL-1ß expression remained at high levels while AMPs and IL-23 increased even more compared with non-lesional skin. In the dermis of non-lesional HS skin, signs of inflammation were barely detectable (vs. AGR), while in the lesional dermis, the number of inflammatory cells and Th1/Th17-related mediators were significantly elevated. CONCLUSIONS: Our findings that non-lesional HS epidermal keratinocytes produce not only AMPs and IL-1ß but also high levels of TNF-α and IL-23 confirm the driver role of keratinocytes in HS pathogenesis and highlight the possible role of keratinocytes in the transformation of non-inflammatory Th17 cells (of healthy AGR skin) into inflammatory cells (of HS) via the production of these mediators. The fact that epidermal TNF-α and IL-23 appear also in non-lesional HS seems to prove these cytokines as excellent therapeutic targets.


Assuntos
Hidradenite Supurativa , Citocinas/metabolismo , Epiderme/patologia , Hidradenite Supurativa/genética , Humanos , Queratinócitos/patologia , Pele/patologia
17.
J Invest Dermatol ; 142(2): 333-342.e6, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34352263

RESUMO

Increased presence of IL-22+ cells in the skin is a characteristic finding in skin barrier defects, such as psoriasis and atopic dermatitis. However, mechanistic insight into effects of IL-22 on epidermal functioning is yet to be elucidated. One crucial step during epidermal differentiation is deimination or citrullination. Here, we show reduced levels of peptidylarginine deiminase 1, an enzyme that converts peptidylarginine into citrulline in lesional psoriatic skin. IL-22 signaling through the IL-22 receptor complex was found to suppress expression of peptidylarginine deiminase 1 in epidermal keratinocytes. Subsequently, total peptidylarginine deiminase activity and extent of protein deimination in keratinocytes treated with IL-22 were reduced together with a significant decrease in deimination of keratin 1 and FLG, both important for epidermal differentiation. Vitamin D and acitretin partly restored the peptidylarginine deiminase 1 defect caused by IL-22. Collectively, we show that IL-22 downregulates deimination, thus identifying a potential target for treatment of skin barrier defects.


Assuntos
Epiderme/patologia , Interleucinas/metabolismo , Proteína-Arginina Desiminase do Tipo 1/genética , Psoríase/genética , Acitretina/farmacologia , Acitretina/uso terapêutico , Biópsia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Citrulinação/efeitos dos fármacos , Citrulinação/genética , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/genética , Dermatite Atópica/patologia , Regulação para Baixo , Epiderme/efeitos dos fármacos , Epiderme/enzimologia , Humanos , Queratina-1/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/enzimologia , Queratinócitos/patologia , Cultura Primária de Células , Proteína-Arginina Desiminase do Tipo 1/metabolismo , Psoríase/tratamento farmacológico , Psoríase/patologia , Vitamina D/farmacologia , Vitamina D/uso terapêutico
18.
J Invest Dermatol ; 142(2): 323-332.e8, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34352264

RESUMO

Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. In this study, we compare two dominant missense mutations in the DSG1 transmembrane domain (TMD), G557R and G562R, causing PPK (DSG1PPK-TMD) and SAM syndrome (DSG1SAM-TMD), respectively, to determine the differing pathomechanisms of these mutants. Expressing the DSG1TMD mutants in a DSG-null background, we use cellular and biochemical assays to reveal the differences in the mechanistic behavior of each mutant. Super-resolution microscopy and functional assays showed a failure by both mutants to assemble desmosomes due to reduced membrane trafficking and lipid raft targeting. DSG1SAM-TMD maintained normal expression levels and turnover relative to wildtype DSG1, but DSG1PPK-TMD lacked stability, leading to increased turnover through lysosomal and proteasomal pathways and reduced expression levels. These results differentiate the underlying pathomechanisms of these disorders, suggesting that DSG1SAM-TMD acts dominant negatively, whereas DSG1PPK-TMD is a loss-of-function mutation causing the milder PPK disease phenotype. These mutants portray the importance of the DSG TMD in desmosome function and suggest that a greater understanding of the desmosomal cadherin TMDs will further our understanding of the role that desmosomes play in epidermal pathophysiology.


Assuntos
Desmogleína 1/genética , Desmossomos/patologia , Epiderme/patologia , Ceratodermia Palmar e Plantar/genética , Adesão Celular/genética , Linhagem Celular Tumoral , Desmogleína 1/metabolismo , Caderinas de Desmossomos/metabolismo , Desmossomos/metabolismo , Epiderme/metabolismo , Humanos , Ceratodermia Palmar e Plantar/patologia , Mutação com Perda de Função , Microdomínios da Membrana/metabolismo , Mutação de Sentido Incorreto , Domínios Proteicos/genética , Estabilidade Proteica
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