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

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.20082242 ◽

2009 ◽

Vol 206 (5) ◽

pp. 1135-1147 ◽

Cited By ~ 322

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.

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Evaluation of a crystallographic surrogate for kallikrein 5 in the discovery of novel inhibitors for Netherton syndrome

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x19003169 ◽

2019 ◽

Vol 75 (5) ◽

pp. 385-391

Author(s):

James H. Thorpe ◽

Emma V. Edgar ◽

Kathrine J. Smith ◽

Xiao Q. Lewell ◽

Monika Rella ◽

...

Keyword(s):

Drug Discovery ◽

Skin Disorder ◽

Skin Barrier ◽

Loss Of Function ◽

Endogenous Inhibitor ◽

X Ray ◽

Netherton Syndrome ◽

Knowledge Based ◽

Potential Strategy ◽

Allergic Manifestations

The inhibition of kallikrein 5 (KLK5) has been identified as a potential strategy for treatment of the genetic skin disorder Netherton syndrome, in which loss-of-function mutations in the SPINK5 gene lead to down-regulation of the endogenous inhibitor LEKTI-1 and profound skin-barrier defects with severe allergic manifestations. To aid in the development of a medicine for this target, an X-ray crystallographic system was developed to facilitate fragment-guided chemistry and knowledge-based drug-discovery approaches. Here, the development of a surrogate crystallographic system in place of KLK5, which proved to be challenging to crystallize, is described. The biochemical robustness of the crystallographic surrogate and the suitability of the system for the study of small nonpeptidic fragments and lead-like molecules are demonstrated.

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Mechanistic insight from murine models of Netherton syndrome

Biological Chemistry ◽

10.1515/hsz-2016-0203 ◽

2016 ◽

Vol 397 (12) ◽

pp. 1223-1228 ◽

Cited By ~ 2

Author(s):

Zela Keuylian ◽

Alain Hovnanian

Keyword(s):

Protease Inhibitor ◽

Serine Protease ◽

Crucial Role ◽

Serine Protease Inhibitor ◽

Murine Models ◽

Loss Of Function ◽

Netherton Syndrome ◽

Mechanistic Insight ◽

Stratified Epithelia

Abstract Protease regulation plays a crucial role in skin homeostasis and inflammation as revealed by the identification of loss-of-function mutations in SPINK5 (serine protease inhibitor of Kazal type 5) in Netherton sydrome (NS). SPINK5 encodes LEKTI (lympho-epithelial Kazal type related inhibitor), a multidomain serine protease inhibitor expressed in all stratified epithelia. Our laboratory has developed a number of murine models which have been instrumental in dissecting the pathogenesis of NS. This minireview discusses the major findings of these models and emphasizes the role of protease regulation, especially kallikrein-related peptidases in NS.

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Stress and Skin: An Overview of Mind Body Therapies as a Treatment Strategy in Dermatology

Dermatology Practical & Conceptual ◽

10.5826/dpc.1104a91 ◽

2021 ◽

pp. e2021091

Author(s):

Rachel Graubard ◽

Ariadna Perez-Sanchez ◽

Rajani Katta

Keyword(s):

Stress Response ◽

Skin Disease ◽

Skin Barrier ◽

Psychosocial Outcomes ◽

Skin Inflammation ◽

The Body ◽

Skin Barrier Function ◽

Beneficial Effects ◽

Potential Benefits ◽

The Mind

Stress has multiple and wide-ranging physiologic and clinical impacts on skin disease. This has led to an interest in mind body therapies as potential adjunct treatments for skin disease. The stress response results in the activation of the endocrine, neurologic, and immune systems, with a resulting cascade of impacts, that are both systemic and cutaneous. The 2 main arms of the stress response are the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. The resultant release of cortisol, catecholamines, and neuropeptides has multiple effects. Clinically, these have been shown to increase skin inflammation, increase itching, impair skin barrier function, impair wound healing, and suppress immunity.Mind body therapies are those that focus on the interaction between the mind and the body, with the goal to influence physical function and impact health. These have been shown to ameliorate some of the harmful physiologic changes attributed to stress or to reduce harmful behaviors. In some cases, such as with biofeedback, they may also result in beneficial physiologic changes. Treatments such as meditation, biofeedback, hypnosis, guided imagery, and others have been evaluated in the treatment of skin disease and have shown some benefits. Although randomized controlled trials are limited, these interventions have shown beneficial effects on itching, psychosocial outcomes, and even skin severity. These interventions have been evaluated in diseases such as atopic dermatitis, psoriasis, trichotillomania, and others. Given the potential benefits, improvements in psychosocial outcomes, and a low risk profile, referral to qualified practitioners or multidisciplinary clinics should be considered for some patients.

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

The Journal of Lipid Research ◽

10.1194/jlr.ra120000639 ◽

2020 ◽

Vol 61 (6) ◽

pp. 859-869 ◽

Cited By ~ 1

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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Is c.1431-12G>A A common European mutation of SPINK5? report of a patient with Netherton Syndrome

Balkan Journal of Medical Genetics ◽

10.1515/bjmg-2016-0040 ◽

2016 ◽

Vol 19 (2) ◽

pp. 81-84 ◽

Cited By ~ 1

Author(s):

R Śmigiel ◽

B Królak-Olejnik ◽

D Śniegórska ◽

A Rozensztrauch ◽

A Szafrańska ◽

...

Keyword(s):

Literature Review ◽

Protease Inhibitor ◽

Skin Disease ◽

Current Knowledge ◽

The Novel ◽

Gene Encoding ◽

Netherton Syndrome ◽

Clinical Description ◽

Polish Patient

Abstract Netherton Syndrome (NS) is a very rare genetic skin disease resulting from defects in the SPINK5 gene (encoding the protease inhibitor lympho-epithelial Kazal type inhibitor 1, LEKTI1). In this report, we provide a detailed clinical description of a Polish patient with two SPINK5 mutations, the novel c.1816_1820+21delinsCT and possibly recurrent c.1431-12G>A. A detailed pathogenesis of Netherton Syndrome, on the basis of literature review, is discussed in the view of current knowledge about the LEKT1 molecular processing and activity.

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Inhibition of human kallikreins 5 and 7 by the serine protease inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI)

Biological Chemistry ◽

10.1515/bc.2005.134 ◽

2005 ◽

Vol 386 (11) ◽

pp. 1173-1184 ◽

Cited By ~ 66

Author(s):

Norman M. Schechter ◽

Eun-Jung Choi ◽

Zhe-Mei Wang ◽

Yasushi Hanakawa ◽

John R. Stanley ◽

...

Keyword(s):

Protease Inhibitor ◽

Serine Protease ◽

Serine Proteases ◽

Equilibrium Constants ◽

Kinetic Studies ◽

Serine Protease Inhibitor ◽

Skin Development ◽

Netherton Syndrome ◽

Specific Association ◽

20 Nm

Abstract LEKTI is a 120-kDa protein that plays an important role in skin development, as mutations affecting LEKTI synthesis underlie Netherton syndrome, an inherited skin disorder producing severe scaling. Its primary sequence indicates that the protein consists of 15 domains, all resembling a Kazal-type serine protease inhibitor. LEKTI and two serine proteases belonging to the human tissue kallikrein (hK) family (hK5 and hK7) are expressed in the granular layer of skin. In this study, we characterize the interaction of two recombinant LEKTI fragments containing three or four intact Kazal domains (domains 6–8 and 9–12) with recombinant rhK5, a trypsin-like protease, and recombinant rhK7, a chymotrypsin-like protease. Both fragments inhibited rhK5 similarly in binding and kinetic studies performed at pH 8.0, as well as pH 5.0, the pH of the stratum corneum where both LEKTI and proteases may function. Inhibition equilibrium constants (K i) measured either directly in concentration-dependent studies or calculated from measured association (k ass) and dissociation (k dis) rate constants were 1.2–5.5 nM at pH 8.0 and 10–20 nM at pH 5.0. At pH 8.0, k ass and k dis values were 4.7×105 M−1 s−1 and 5.5×10−4 s−1, and at pH 5.0 they were 4.0×104 M−1 s−1 and 4.3×10−4 s−1, respectively. The low K i and k dis values (t 1/2 of 20–25 min) indicate tight and specific association. Only fragment 6–9′ was a good inhibitor of rhK7, demonstrating a K i of 11 nM at pH 8.0 in a reaction that was rapidly reversible. These results show that LEKTI, at least in fragment form, is a potent inhibitor of rhK5 and that this protease may be a target of LEKTI in human skin.

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