Persistent kallikrein 5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity

Zhu, Yanan; Underwood, Joanne; Macmillan, Derek; Shariff, Leila; O'Shaughnessy, R; Harper, John; Pickard, C.; Friedmann, Peter S.; Healy, Eugene; Di, Wei‐Li

doi:10.1016/j.jaci.2017.01.025

Cited by 53 publications

(62 citation statements)

References 48 publications

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“…Immunohistochemical staining for KLK5 in healthy, NS, AD, APSS and SD samples resembled activography staining (Figure B), consistent with the fact that KLK5 plays important roles in NS, AD and APSS pathology. KLK6 colocalizes with KLK5, and its staining is like activography (Figure C).…”

Section: Resultssupporting

confidence: 80%

Activography reveals aberrant proteolysis in desquamating diseases of differing backgrounds

Zingkou

Pampalakis

Kiritsi

et al. 2019

Experimental Dermatology

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The role of epidermal proteolysis in overdesquamation was revealed in Netherton syndrome, a rare ichthyosis due to genetic deficiency of the LEKTI inhibitor of serine proteases. Recently, we developed activography, a new histochemical method, to spatially localize and semiquantitatively assess proteolytic activities using activity‐based probes. Activography provides specificity and versatility compared to in situ zymography, the only available method to determine enzymatic activities in tissue biopsies. Here, activography was validated in skin biopsies obtained from an array of distinct disorders and compared with in situ zymography. Activography provides a methodological advancement due to its simplicity and specificity and can be readily adapted as a routine diagnostic assay. Interestingly, the levels of epidermal proteolysis correlated with the degree of desquamation independent of skin pathology. Thus, deregulated epidermal proteolysis likely represents a universal mechanism underlying aberrant desquamation.

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Section: Resultssupporting

confidence: 80%

Activography reveals aberrant proteolysis in desquamating diseases of differing backgrounds

Zingkou

Pampalakis

Kiritsi

et al. 2019

Experimental Dermatology

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“…Neutralization of pH in the SC may also trigger PAR2 activation through induction of serine protease activity . Specifically, upregulation of KLK‐5 in alkalinized mouse skin may act through PAR2 to decrease barrier function, though conflicting data show KLK‐5 may act independently of PAR2 as well . Furthermore, mice with knocked out CAP1/Prss8 (an activator of PAR2) die due to dehydration and this was associated with increased transepidermal water loss.…”

Section: Methods and Resultsmentioning

confidence: 99%

“…This could help make sense of PAR2 involvement with numerous molecular pathways. Additionally, emerging evidence of desensitization effects to PAR2 after repeated stimulation may complicate interpretation of different study models …”

Section: Discussion and Clinical Correlationsmentioning

confidence: 99%

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Update on protease‐activated receptor 2 in cutaneous barrier, differentiation, tumorigenesis and pigmentation, and its role in related dermatologic diseases

Henehan

Benedetto

2019

Experimental Dermatology

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Protease‐activated receptor 2 (PAR2) is a transmembrane receptor expressed by multiple tissues, including skin, with rapidly expanding knowledge regarding its roles. In the skin, PAR2 has extensively documented effects in promoting Th2 inflammation and pruritus; and its role in atopic dermatitis continues to be thoroughly studied. Numerous new investigations have shown a more complex range of activities potentially related to dermatologic diseases. Goal of this review is to outline emerging effects of PAR2 activation in the skin other than those related to immunologic and pruritic functions. Specifically, this work seeks to summarize current knowledge (and gaps) of PAR2 as a regulator of epidermal barrier, keratinocyte differentiation, cutaneous tumorigenesis and pigmentation. Additional focus will be placed on possible involvement in dermatologic disease and emergence as a therapeutic target.

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“…Other factors that have been associated with a defective epidermal barrier in AD are an altered lipid organization and ceramide composition with an increase in the proportion of short-chain ceramides in the context of Th2 inflammation [63-66]. Furthermore, an imbalance of protease inhibitors, e.g., reduced LEKTI expression, and proteases resulting in a high activity of both endogenous and exogenous proteases with subsequent PAR 2 activation and increased TSLP production, is thought to contribute to AD pathogenesis [67-70]. In addition to the SC, tight junctions formed by complex multiprotein structures are an important component of the skin barrier as they regulate the paracellular passage of water, ions, and solutes [71].…”

Section: Pathogenenic Mechanismsmentioning

confidence: 99%

Atopic Dermatitis: Collegium Internationale Allergologicum (CIA) Update 2019

Simon

Wollenberg

Renz

et al. 2019

Int Arch Allergy Immunol

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Atopic dermatitis (AD) is a chronic inflammatory skin disease presenting with recurrent eczematous lesions and intense pruritus. It is common and affects both children and adults, often beginning in infancy. Due to the unpredictable disease course, its visible skin lesions, itching and scratching followed by sleeplessness, other associated atopic diseases, and behavioral and psychiatric disorders, AD is an immense burden for patients and caregivers. AD is determined by a genetic predisposition characterized by an impaired skin barrier and a T-helper-2-predominant inflammation. Restoration of the skin barrier is the main approach for treating and preventing AD. In order to cope with acute flares, usually topical corticosteroids (TCS) are applied, while topical calcineurin inhibitors (TCI) are used mainly for maintenance therapy. There is a small group of patients who are refractory to TCS and TCI and require systemic immunosuppressive drugs such as ciclosporin. Novel, targeted therapies are under clinical investigation, among which an anti-IL-4/IL-13 receptor antibody has recently been approved in several countries. As we learn to understand the pathomechanisms of AD, the characteristics of the different patient subgroups, and the effectiveness of various targeted therapies, a personalized treatment ensuring the best efficacy and safety and, probably, a disease-modifying effect will result.

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Persistent kallikrein 5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity

Abstract: 27Background: Up-regulation of kallikreins (KLK) including KLK5 has been reported in atopic 28

Cited by 53 publications

References 48 publications

Activography reveals aberrant proteolysis in desquamating diseases of differing backgrounds

Activography reveals aberrant proteolysis in desquamating diseases of differing backgrounds

Update on protease‐activated receptor 2 in cutaneous barrier, differentiation, tumorigenesis and pigmentation, and its role in related dermatologic diseases

Atopic Dermatitis: Collegium Internationale Allergologicum (CIA) Update 2019

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