Filaggrin Plays Critical Role in Skin Barrier Health

Abstract Background – The skin barrier is important in the pathogenesis of atopic dermatitis and stratum corneum lipids have a critical role. Skin surface lipids have been largely overlooked but also contribute to barrier function. An untargeted approach was used to compare the skin surface lipids from atopic and non-atopic West Highland White terrier dogs. The primary hypothesis was that a difference in the lipidome of atopic and non-atopic dogs would be found and the secondary hypothesis was that affected and unaffected skin would differ in lipid profile.Results – Thirty-nine dogs were classified into one of four disease status groups based on strict criteria. Samples for lipid analysis were collected from affected and unaffected skin, and liquid chromatography/mass spectrometry found 421 lipid soluble features. Ten lipids were positively identified. Statistical analysis could not distinguish between non-atopic and atopic dogs. Partial least squares-discriminant analysis revealed a difference in the lipid profiles from affected and non-affected skin irrespective of disease status. Conclusions – An untargeted approach found a large array of unidentified lipids from the skin surface. There was a difference in the lipidome between affected and unaffected skin that was not related to disease status. Investigation into the lipidome of the skin surface in health and disease is an emerging area of research which could have clinical and therapeutic applications.

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Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages

Cells ◽

10.3390/cells9081753 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1753 ◽

Cited By ~ 1

Author(s):

Bhakta Prasad Gaire ◽

Chi-Ho Lee ◽

Wondong Kim ◽

Arjun Sapkota ◽

Do Yup Lee ◽

...

Keyword(s):

Lysophosphatidic Acid ◽

Nlrp3 Inflammasome ◽

Critical Role ◽

Skin Barrier ◽

Underlying Mechanism ◽

Inflammasome Activation ◽

Lpa Receptor ◽

Nlrp3 Inflammasome Activation ◽

Injured Skin

The pathogenesis of psoriasis, an immune-mediated chronic skin barrier disease, is not fully understood yet. Here, we identified lysophosphatidic acid (LPA) receptor 5 (LPA5)-mediated signaling as a novel pathogenic factor in psoriasis using an imiquimod-induced psoriasis mouse model. Amounts of most LPA species were markedly elevated in injured skin of psoriasis mice, along with LPA5 upregulation in injured skin. Suppressing the activity of LPA5 with TCLPA5, a selective LPA5 antagonist, improved psoriasis symptoms, including ear thickening, skin erythema, and skin scaling in imiquimod-challenged mice. TCLPA5 administration attenuated dermal infiltration of macrophages that were found as the major cell type for LPA5 upregulation in psoriasis lesions. Notably, TCLPA5 administration attenuated the upregulation of macrophage NLRP3 in injured skin of mice with imiquimod-induced psoriasis. This critical role of LPA5 in macrophage NLRP3 was further addressed using lipopolysaccharide-primed bone marrow-derived macrophages. LPA exposure activated NLRP3 inflammasome in lipopolysaccharide-primed cells, which was evidenced by NLRP3 upregulation, caspase-1 activation, and IL-1β maturation/secretion. This LPA-driven NLRP3 inflammasome activation in lipopolysaccharide-primed cells was significantly attenuated upon LPA5 knockdown. Overall, our findings establish a pathogenic role of LPA5 in psoriasis along with an underlying mechanism, further suggesting LPA5 antagonism as a potential strategy to treat psoriasis.

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Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand–dependent terminal keratinocyte differentiation

Journal of Experimental Medicine ◽

10.1084/jem.20112258 ◽

2012 ◽

Vol 209 (6) ◽

pp. 1105-1119 ◽

Cited By ~ 110

Author(s):

Claus-Werner Franzke ◽

Cristina Cobzaru ◽

Antigoni Triantafyllopoulou ◽

Stefanie Löffek ◽

Keisuke Horiuchi ◽

...

Keyword(s):

Immune Cell ◽

Tissue Injury ◽

Critical Role ◽

Growth Factor Receptor ◽

Skin Barrier ◽

Skin Inflammation ◽

Transepidermal Water Loss ◽

Epidermal Differentiation ◽

Keratinocyte Differentiation ◽

Epidermal Barrier

ADAM17 (a disintegrin and metalloproteinase 17) is ubiquitously expressed and cleaves membrane proteins, such as epidermal growth factor receptor (EGFR) ligands, l-selectin, and TNF, from the cell surface, thus regulating responses to tissue injury and inflammation. However, little is currently known about its role in skin homeostasis. We show that mice lacking ADAM17 in keratinocytes (A17ΔKC) have a normal epidermal barrier and skin architecture at birth but develop pronounced defects in epidermal barrier integrity soon after birth and develop chronic dermatitis as adults. The dysregulated expression of epidermal differentiation proteins becomes evident 2 d after birth, followed by reduced transglutaminase (TGM) activity, transepidermal water loss, up-regulation of the proinflammatory cytokine IL-36α, and inflammatory immune cell infiltration. Activation of the EGFR was strongly reduced in A17ΔKC skin, and topical treatment of A17ΔKC mice with recombinant TGF-α significantly improved TGM activity and decreased skin inflammation. Finally, we show that mice lacking the EGFR in keratinocytes (EgfrΔKC) closely resembled A17ΔKC mice. Collectively, these results identify a previously unappreciated critical role of the ADAM17–EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier and suggest that this pathway could represent a good target for treatment of epidermal barrier defects.

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Phase behavior of skin lipid mixtures: the effect of cholesterol on lipid organization

Soft Matter ◽

10.1039/c4sm02786h ◽

2015 ◽

Vol 11 (21) ◽

pp. 4326-4336 ◽

Cited By ~ 29

Author(s):

E. H. Mojumdar ◽

G. S. Gooris ◽

J. A. Bouwstra

Keyword(s):

Stratum Corneum ◽

Phase Behavior ◽

Critical Role ◽

Skin Barrier ◽

Lipid Matrix ◽

Skin Lipid ◽

Lipid Mixtures ◽

Lipid Organization

The lipid matrix in the stratum corneum (SC), the upper layer of the skin, plays a critical role in the skin barrier.

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Potential Therapeutic Approaches through Modulating the Autophagy Process for Skin Barrier Dysfunction

International Journal of Molecular Sciences ◽

10.3390/ijms22157869 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7869

Author(s):

Min Sik Choi ◽

Yoon-Jee Chae ◽

Ji Woong Choi ◽

Ji-Eun Chang

Keyword(s):

Defense Mechanisms ◽

Inflammatory Diseases ◽

Critical Role ◽

Skin Barrier ◽

Skin Aging ◽

The Body ◽

Therapeutic Approaches ◽

Barrier Dysfunction ◽

The Relationship ◽

Endogenous Defense

Autophagy is an attractive process to researchers who are seeking novel potential treatments for various diseases. Autophagy plays a critical role in degrading damaged cellular organelles, supporting normal cell development, and maintaining cellular homeostasis. Because of the various effects of autophagy, recent human genome research has focused on evaluating the relationship between autophagy and a wide variety of diseases, such as autoimmune diseases, cancers, and inflammatory diseases. The skin is the largest organ in the body and provides the first line of defense against environmental hazards, including UV damage, chemical toxins, injuries, oxidative stress, and microorganisms. Autophagy takes part in endogenous defense mechanisms by controlling skin homeostasis. In this manner, regulating autophagy might contribute to the treatment of skin barrier dysfunctions. Various studies are ongoing to elucidate the association between autophagy and skin-related diseases in order to find potential therapeutic approaches. However, little evidence has been gathered about the relationship between autophagy and the skin. In this review, we highlight the previous findings of autophagy and skin barrier disorders and suggest potential therapeutic strategies. The recent research regarding autophagy in acne and skin aging is also discussed.

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Dexamethasone Effect on Embryonic Chick Respiratory Epithelium

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053905 ◽

1982 ◽

Vol 40 ◽

pp. 248-249

Author(s):

M.R. Richter ◽

R.V. Blystone

Keyword(s):

Lung Development ◽

Critical Role ◽

Respiratory Epithelium ◽

Chick Embryos ◽

Embryonic Chick ◽

White Leghorn ◽

Lung Maturation ◽

Synthetic Analogs ◽

Lung Physiology ◽

Avian Lung

Dexamethasone and other synthetic analogs of corticosteroids have been employed clinically as enhancers of lung development. The mechanism(s) by which this steroid induction of later lung maturation operates is not clear. This study reports the effect on lung epithelia of dexamethasone administered at different intervals during development. White Leghorn chick embryos were used so as to remove possible maternal and placental influences on the exogenously applied steroid. Avian lung architecture does vary from mammals; however, respiratory surfactant produced by the lung epithelia serves an equally critical role in avian lung physiology.

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An atomic resolution study of a carbide phase in platinum

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100120503 ◽

1992 ◽

Vol 50 (1) ◽

pp. 20-21

Author(s):

M.J. Witcomb ◽

M.A. O'Keefe ◽

CJ. Echer ◽

C. Nelson ◽

J.H. Turner ◽

...

Keyword(s):

Solid Solution ◽

Carbon Atom ◽

Carbide Phase ◽

Structural Changes ◽

Critical Role ◽

Alloy System ◽

Atomic Resolution ◽

Excess Carbon ◽

Interstitial Carbon ◽

Resolution Study

Under normal circumstances, Pt dissolves only a very small amount of interstitial carbon in solid solution. Even so, an appropriate quench/age treatment leads to the formation of stable Pt2C {100} plate precipitates. Excess (quenched-in) vacancies play a critical role in the process by accommodating the volume and structural changes that accompany the transformation. This alloy system exhibits other interesting properties. Due to a large vacancy/carbon atom binding energy, Pt can absorb excess carbon at high temperatures in a carburizing atmosphere. In regions rich in carbon and vacancies, another carbide phase, Pt7C which undergoes an order-disorder reaction was formed. The present study of Pt carburized at 1160°C and aged at 515°C shows that other carbides in the PtxC series can be produced.

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Changes in corneocyte element concentrations occur in skin inner stratum corneum

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100134326 ◽

1990 ◽

Vol 48 (2) ◽

pp. 146-147

Author(s):

R. R. Warner

Keyword(s):

Stratum Corneum ◽

Human Skin ◽

Element Concentration ◽

Skin Barrier ◽

Barrier Properties ◽

Brick Wall ◽

Inorganic Elements ◽

Dry Skin ◽

Skin Biopsies ◽

Intercellular Lipid

Keratinocytes undergo maturation during their transit through the viable layers of skin, and then abruptly transform into flattened, anuclear corneocytes that constitute the cellular component of the skin barrier, the stratum corneum (SC). The SC is generally considered to be homogeneous in its structure and barrier properties, and is often shown schematically as a featureless brick wall, the “bricks” being the corneocytes, the “mortar” being intercellular lipid. Previously we showed the outer SC was not homogeneous in its composition, but contained steep gradients of the physiological inorganic elements Na, K and Cl, likely originating from sweat salts. Here we show the innermost corneocytes in human skin are also heterogeneous in composition, undergoing systematic changes in intracellular element concentration during transit into the interior of the SC.Human skin biopsies were taken from the lower leg of individuals with both “good” and “dry” skin and plunge-frozen in a stirred, cooled isopentane/propane mixture.

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Quantitative Model-Based Image Analysis of NuMa Distribution Links Nuclear Organization with Cell Phenotype

Microscopy and Microanalysis ◽

10.1017/s1431927600028968 ◽

2001 ◽

Vol 7 (S2) ◽

pp. 578-579

Author(s):

David W. Knowles ◽

Sophie A. Lelièvre ◽

Carlos Ortiz de Solόrzano ◽

Stephen J. Lockett ◽

Mina J. Bissell ◽

...

Keyword(s):

Image Analysis ◽

Mammary Epithelial Cells ◽

Nuclear Organization ◽

Critical Role ◽

Quantitative Model ◽

Mammary Epithelial ◽

Cell Phenotype ◽

Proliferating Cells ◽

Mitotic Apparatus ◽

Model Based

The extracellular matrix (ECM) plays a critical role in directing cell behaviour and morphogenesis by regulating gene expression and nuclear organization. Using non-malignant (S1) human mammary epithelial cells (HMECs), it was previously shown that ECM-induced morphogenesis is accompanied by the redistribution of nuclear mitotic apparatus (NuMA) protein from a diffuse pattern in proliferating cells, to a multi-focal pattern as HMECs growth arrested and completed morphogenesis . A process taking 10 to 14 days.To further investigate the link between NuMA distribution and the growth stage of HMECs, we have investigated the distribution of NuMA in non-malignant S1 cells and their malignant, T4, counter-part using a novel model-based image analysis technique. This technique, based on a multi-scale Gaussian blur analysis (Figure 1), quantifies the size of punctate features in an image. Cells were cultured in the presence and absence of a reconstituted basement membrane (rBM) and imaged in 3D using confocal microscopy, for fluorescently labeled monoclonal antibodies to NuMA (fαNuMA) and fluorescently labeled total DNA.

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Crystal structures of Magnaporthe oryzae trehalose-6-phosphate synthase (MoTps1) suggest a model for catalytic process of Tps1

Biochemical Journal ◽

10.1042/bcj20190289 ◽

2019 ◽

Vol 476 (21) ◽

pp. 3227-3240 ◽

Cited By ~ 1

Author(s):

Shanshan Wang ◽

Yanxiang Zhao ◽

Long Yi ◽

Minghe Shen ◽

Chao Wang ◽

...

Keyword(s):

Crystal Structures ◽

Conformational Changes ◽

Magnaporthe Oryzae ◽

Structural Information ◽

Complex Structure ◽

Critical Role ◽

Catalytic Process ◽

Structural Basis ◽

Salt Bridges ◽

Terminal Domain

Trehalose-6-phosphate (T6P) synthase (Tps1) catalyzes the formation of T6P from UDP-glucose (UDPG) (or GDPG, etc.) and glucose-6-phosphate (G6P), and structural basis of this process has not been well studied. MoTps1 (Magnaporthe oryzae Tps1) plays a critical role in carbon and nitrogen metabolism, but its structural information is unknown. Here we present the crystal structures of MoTps1 apo, binary (with UDPG) and ternary (with UDPG/G6P or UDP/T6P) complexes. MoTps1 consists of two modified Rossmann-fold domains and a catalytic center in-between. Unlike Escherichia coli OtsA (EcOtsA, the Tps1 of E. coli), MoTps1 exists as a mixture of monomer, dimer, and oligomer in solution. Inter-chain salt bridges, which are not fully conserved in EcOtsA, play primary roles in MoTps1 oligomerization. Binding of UDPG by MoTps1 C-terminal domain modifies the substrate pocket of MoTps1. In the MoTps1 ternary complex structure, UDP and T6P, the products of UDPG and G6P, are detected, and substantial conformational rearrangements of N-terminal domain, including structural reshuffling (β3–β4 loop to α0 helix) and movement of a ‘shift region' towards the catalytic centre, are observed. These conformational changes render MoTps1 to a ‘closed' state compared with its ‘open' state in apo or UDPG complex structures. By solving the EcOtsA apo structure, we confirmed that similar ligand binding induced conformational changes also exist in EcOtsA, although no structural reshuffling involved. Based on our research and previous studies, we present a model for the catalytic process of Tps1. Our research provides novel information on MoTps1, Tps1 family, and structure-based antifungal drug design.

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