scholarly journals Kallikrein 5 induces atopic dermatitis–like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome

2009 ◽  
Vol 206 (5) ◽  
pp. 1135-1147 ◽  
Author(s):  
Anaïs Briot ◽  
Céline Deraison ◽  
Matthieu Lacroix ◽  
Chrystelle Bonnart ◽  
Aurélie Robin ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Protease Inhibitor ◽  
Adaptive Immune System ◽  
Skin Barrier ◽  
Skin Inflammation ◽  
Nuclear Factor Κb ◽  
Thymic Stromal Lymphopoietin ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Netherton Syndrome

Netherton syndrome (NS) is a severe genetic skin disease with constant atopic manifestations that is caused by mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, which encodes the protease inhibitor lymphoepithelial Kazal-type–related inhibitor (LEKTI). Lack of LEKTI causes stratum corneum detachment secondary to epidermal proteases hyperactivity. This skin barrier defect favors allergen absorption and is generally regarded as the underlying cause for atopy in NS. We show for the first time that the pro-Th2 cytokine thymic stromal lymphopoietin (TSLP), the thymus and activation-regulated chemokine, and the macrophage-derived chemokine are overexpressed in LEKTI-deficient epidermis. This is part of an original biological cascade in which unregulated kallikrein (KLK) 5 directly activates proteinase-activated receptor 2 and induces nuclear factor κB–mediated overexpression of TSLP, intercellular adhesion molecule 1, tumor necrosis factor α, and IL8. This proinflammatory and proallergic pathway is independent of the primary epithelial failure and is activated under basal conditions in NS keratinocytes. This cell-autonomous process is already established in the epidermis of Spink5−/− embryos, and the resulting proinflammatory microenvironment leads to eosinophilic and mast cell infiltration in a skin graft model in nude mice. Collectively, these data establish that uncontrolled KLK5 activity in NS epidermis can trigger atopic dermatitis (AD)–like lesions, independently of the environment and the adaptive immune system. They illustrate the crucial role of protease signaling in skin inflammation and point to new therapeutic targets for NS as well as candidate genes for AD and atopy.

Netherton syndrome: defective kallikrein inhibition in the skin leads to skin inflammation and allergy

2014 ◽  
Vol 395 (9) ◽  
pp. 945-958 ◽  
Author(s):  
Laetitia Furio ◽  
Alain Hovnanian
Keyword(s):  
Protease Inhibitor ◽  
Mouse Models ◽  
Skin Disease ◽  
Skin Barrier ◽  
Skin Inflammation ◽  
Serine Protease Inhibitor ◽  
Loss Of Function ◽  
Netherton Syndrome ◽  
Barrier Defect ◽  
Allergic Manifestations

Abstract Netherton syndrome (NS) is an orphan genetic skin disease with a profound skin barrier defect and severe allergic manifestations. NS is caused by loss of function mutations in SPINK5 encoding lympho-epithelial Kazal-type inhibitor (LEKTI), a secreted multi-domain serine protease inhibitor expressed in stratified epithelia. Studies in mouse models and in NS patients have established that unopposed kallikrein 5 activity triggers stratum corneum detachment and activates PAR-2 signaling, leading to the autonomous production of pro-allergic and pro-inflammatory mediators. This emerging knowledge on NS pathogenesis has highlighted a central role for protease regulation in skin homeostasis but also in the complexity of the disease, and holds the promise of new specific treatments.

Inhaled nitric oxide protects against hyperoxia-induced apoptosis in rat lungs

1999 ◽  
Vol 277 (3) ◽  
pp. L596-L605 ◽  
Author(s):  
Clare E. Howlett ◽  
James S. Hutchison ◽  
John P. Veinot ◽  
Aaron Chiu ◽  
Pradeep Merchant ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nuclear Factor Κb ◽  
Inhaled Nitric Oxide ◽  
Intercellular Adhesion Molecule ◽  
Activator Protein 1 ◽  
Intercellular Adhesion Molecule 1 ◽  
Vascular Leak ◽  
Induced Apoptosis ◽  
Apoptosis And Inflammation ◽  
First Time

Inhaled nitric oxide (NO), frequently administered in combination with hyperoxic gas mixtures, was recently shown to protect against the injurious consequences of prolonged hyperoxia. We investigated the possibility that this protective effect is attributable to the ability of NO to block pulmonary apoptosis. We show that rats exposed to 100% O2for 60 h develop severe lung injury consisting of pronounced vascular leak and alveolar apoptosis as inferred from the presence of positive terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and DNA ladders in agarose gels and a decrease in constitutive procaspase-3 levels. However, the inclusion of NO (20 parts/million) in the hyperoxic gas mixture significantly attenuated both the vascular leak and apoptosis. NO reversed the hyperoxia-associated changes in the activity of the redox-sensitive transcription factors nuclear factor-κB, activator protein-1, and Sp1 after 24 h, lowered intercellular adhesion molecule-1 levels, and increased glutathione content. We therefore show, for the first time, that NO can protect against both hyperoxia-induced apoptosis and inflammation. The data suggest that this protection may occur at the transcriptional and caspase-activation levels.

scholarly journals Resveratrol prevents TNF-α-induced VCAM-1 and ICAM-1 upregulation in endothelial progenitor cells via reduction of NF-κB activation

2020 ◽  
Vol 48 (9) ◽  
pp. 030006052094513
Author(s):  
Yefei Zhang ◽  
Huahua Liu ◽  
Weiliang Tang ◽  
Qiongya Qiu ◽  
Jiahao Peng
Keyword(s):  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Adhesion Molecule ◽  
Nuclear Factor Κb ◽  
Intercellular Adhesion Molecule ◽  
Adhesion Assay ◽  
Intercellular Adhesion Molecule 1 ◽  
Endothelial Progenitor ◽  
Tnf Α ◽  
Factor Α

Objective To assess the effects of resveratrol (RSV) on expression of adhesion molecules in endothelial progenitor cells (EPCs) following tumor necrosis factor-α (TNF-α) stimulation. Methods EPCs were treated with RSV and stimulated with TNF-α. A mononuclear cell (MNC) adhesion assay was used to assess the effects of RSV on TNF-α-induced MNC adhesion. Vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin expression levels and nuclear factor κB (NF-κB) activation were assessed by immunoblotting. Results MNC adhesion to TNF-α-treated EPCs and VCAM-1/ICAM-1/E-selectin levels in EPCs were increased following TNF-α stimulation and decreased following RSV treatment. TNF-α enhanced NF-κB inhibitor α (IκB-α) phosphorylation in the cytosol as well as nuclear NF-κB p65 levels, both of which were decreased by RSV. Conclusions These findings provide new insights into RSV’s anti-inflammatory and anti-atherosclerotic effects. RSV’s mechanism of action might involve downregulation of VCAM-1, ICAM-1 and E-selectin by partial blockade of TNF-α-induced NF-κB activation and IκB-α phosphorylation in EPCs.

scholarly journals Bacterial skin colonization and infections in patients with atopic dermatitis

2012 ◽  
Vol 87 (5) ◽  
pp. 729-734 ◽  
Author(s):  
Vanessa Petry ◽  
Giancarlo Resende Bessa ◽  
Claudia Schermann Poziomczyck ◽  
Caio Fernando de Oliveira ◽  
Magda Blessmann Weber ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Secondary Infection ◽  
Skin Barrier ◽  
Skin Inflammation ◽  
Skin Surface ◽  
Number Of Children ◽  
Chronic Skin ◽  
Systemic Antibiotics

Atopic Dermatitis is a chronic inflammatory skin disease that affects a large number of children and adults. The disease results from an interaction between genetic predisposition, host environment, skin barrier defects, and immunological factors. A major aggravating factor associated with Atopic Dermatitis is the presence of microorganisms on the patient's skin surface. Staphylococcus aureus and Streptococcus pyogenes, for instance, can exacerbate chronic skin inflammation. As a result, antimicrobials have often been prescribed to control the acute phase of the disease. However, increased bacterial resistance to antimicrobial agents has made it difficult for dermatologists to prescribe appropriate medication. In the presence of disseminated dermatitis with secondary infection, systemic antibiotics need to be prescribed; however, treatment should be individualized, in an attempt to find the most effective antibiotic with fewer side effects. Also, the medication should be used for as short as possible in order to minimize bacterial resistance.

Mechanism by which H-2g, a glucose analog of blood group H antigen, mediates angiogenesis

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2343-2349 ◽  
Author(s):  
Kui Zhu ◽  
Mohammed Asif Amin ◽  
Yuanyuan Zha ◽  
Lisa A. Harlow ◽  
Alisa E. Koch
Keyword(s):  
Growth Factor ◽  
Critical Role ◽  
Aortic Ring ◽  
Nuclear Factor Κb ◽  
Janus Kinase ◽  
Intercellular Adhesion Molecule ◽  
Soluble Form ◽  
Intercellular Adhesion Molecule 1

AbstractThe 4A11 antigen is a unique cytokine-inducible antigen up-regulated on rheumatoid arthritis (RA) synovial endothelial cells (ECs) compared with normal ECs. Previously, we showed that in soluble form, this antigen, Lewisy-6/H-5-2 (Ley/H) or its glucose analog, 2-fucosyl lactose (H-2g), induced the expression of EC intercellular adhesion molecule-1 (ICAM-1) and leukocyte-endothelial adhesion through the Janus kinase 2 (JAK2)–signal transducer and activator of transcription 3 (STAT3) pathway. Currently, we show that H-2g induces release of EC angiogenic basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), an effect inhibited by decoy nuclear factor κB (NFκB) oligodeoxynucleotide (ODN). JAK2 and phosphoinositide-3 kinase (PI3K) are 2 upstream kinases of NFκB activated by H-2g, as confirmed by an inhibitor of kappa B kinase (IKKβ) assay. In vitro, H-2g induces vascular sprouting in the rat aortic ring model, whereas blockade of JAK2, PI3K, or NFκB inhibits sprouting. Likewise, in the in vivo mouse Matrigel plug angiogenesis assay, chemical inhibitors and antisense or decoy ODNs of JAK2, PI3K, or NFκB decrease angiogenesis, confirming the importance of these pathways in H-2g–induced EC signaling. The critical role of Ley/H involvement in angiogenesis and its signaling pathways may provide new targets for therapy of diseases characterized by pathologic neovascularization.

scholarly journals Ex-Vivo Skin Explant Culture Is a Model for TSLP-Mediated Skin Barrier Immunity

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1237
Author(s):  
Thomas Bauer ◽  
Daniela Gubi ◽  
Jörg Klufa ◽  
Philipp Novoszel ◽  
Martin Holcmann ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Ex Vivo ◽  
Skin Barrier ◽  
Skin Inflammation ◽  
The Body ◽  
Suitable Model ◽  
Ex Vivo Model ◽  
Egfr Inhibition ◽  
Explant Cultures ◽  
Barrier Immunity

The skin is the outermost barrier protecting the body from pathogenic invasion and environmental insults. Its breakdown initiates the start of skin inflammation. The epidermal growth factor (EGFR) on keratinocytes protects this barrier, and its dysfunction leads to atopic dermatitis-like skin disease. One of the initial cytokines expressed upon skin barrier breach and during atopic dermatitis is TSLP. Here, we describe the expression and secretion of TSLP during EGFR inhibition and present an ex-vivo model, which mimics the early events after barrier insult. Skin explants floated on culture medium at 32 °C released TSLP in parallel to the activation of the resident Langerhans cell network. We could further show the up-regulation and activation of the AP-1 family of transcription factors during atopic-like skin inflammation and its involvement in TSLP production from the skin explant cultures. Inhibition of the c-Jun N-terminal kinase pathway led to a dose-dependent blunting of TSLP release. These data indicate the involvement of AP-1 during the early stages of atopic-like skin inflammation and highlight a novel therapeutic approach by targeting it. Therefore, skin explant cultures mimic the early events during skin barrier immunity and provide a suitable model to test therapeutic intervention.

Cerulein upregulates ICAM-1 in pancreatic acinar cells, which mediates neutrophil adhesion to these cells

2000 ◽  
Vol 279 (4) ◽  
pp. G666-G676 ◽  
Author(s):  
Vjekoslav Zaninovic ◽  
Anna S. Gukovskaya ◽  
Ilya Gukovsky ◽  
Michelle Mouria ◽  
Stephen J. Pandol
Keyword(s):  
Acinar Cells ◽  
Neutrophil Infiltration ◽  
Nuclear Factor Κb ◽  
Pancreatic Acinar Cells ◽  
Intercellular Adhesion Molecule ◽  
Neutrophil Adhesion ◽  
Adhesion Assay ◽  
Intercellular Adhesion Molecule 1 ◽  
Basal Expression ◽  
Activation Of Transcription

Neutrophil infiltration into the pancreas is a key event in pancreatitis. Here we show that intercellular adhesion molecule-1 (ICAM-1), which regulates neutrophil adhesion, is present on rat pancreatic acinar cells, is upregulated by a hormone (cerulein) and mediates direct binding of neutrophils to acinar cells. ICAM-1 was upregulated in pancreas of rats with experimental pancreatitis induced by supramaximal doses of cerulein. Furthermore, cerulein time and dose dependently stimulated expression of ICAM-1 mRNA and protein in isolated pancreatic acinar cells. Inhibitory analysis showed that activation of transcription factor nuclear factor-κB (NF-κB) was involved in ICAM-1 upregulation by cerulein, but NF-κB did not mediate basal expression of ICAM-1 mRNA in acinar cells. With an adhesion assay, we found that neutrophils bind to isolated pancreatic acinar cells and that cerulein upregulates the extent of adhesion. Neutralizing ICAM-1 antibody blocked neutrophil binding to both control and cerulein-stimulated acinar cells, suggesting ICAM-1 involvement in this adhesion. Thus the acinar cell is capable of targeting neutrophils to its surface, a process that may be important for inflammatory and cell death responses in pancreatitis and other pancreatic disorders.

scholarly journals Skin barrier lipid enzyme activity in Netherton patients is associated with protease activity and ceramide abnormalities

2020 ◽  
Vol 61 (6) ◽  
pp. 859-869 ◽  
Author(s):  
Jeroen van Smeden ◽  
Hanin Al-Khakany ◽  
Yichen Wang ◽  
Dani Visscher ◽  
Nicole Stephens ◽  
...  
Keyword(s):  
Serine Protease ◽  
Protease Activity ◽  
Skin Barrier ◽  
Skin Inflammation ◽  
Acid Sphingomyelinase ◽  
Netherton Syndrome ◽  
Serine Protease Activity ◽  
In Situ Zymography ◽  
Ichthyosis Linearis Circumflexa

Individuals with Netherton syndrome (NTS) have increased serine protease activity, which strongly impacts the barrier function of the skin epidermis and leads to skin inflammation. Here, we investigated how serine protease activity in NTS correlates with changes in the stratum corneum (SC) ceramides, which are crucial components of the skin barrier. We examined two key enzymes involved in epidermal ceramide biosynthesis, β-glucocerebrosidase (GBA) and acid-sphingomyelinase (ASM). We compared in situ expression levels and activities of GBA and ASM between NTS patients and controls and correlated the expression and activities with i) SC ceramide profiles, ii) in situ serine protease activity, and iii) clinical presentation of patients. Using activity-based probe labeling, we visualized and localized active epidermal GBA, and a newly developed in situ zymography method enabled us to visualize and localize active ASM. Reduction in active GBA in NTS patients coincided with increased ASM activity, particularly in areas with increased serine protease activity. NTS patients with scaly erythroderma exhibited more pronounced anomalies in GBA and ASM activities than patients with ichthyosis linearis circumflexa. They also displayed a stronger increase in SC ceramides processed via ASM. We conclude that changes in the localization of active GBA and ASM correlate with i) altered SC ceramide composition in NTS patients, ii) local serine protease activity, and iii) the clinical manifestation of NTS.

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