Abstract
Background: Activation of protease-activated receptor-2 (PAR2) has been implicated in inflammation, pruritus, and skin barrier regulation, all characteristics of atopic dermatitis (AD), as well as Netherton syndrome which has similar characteristics. However, understanding the precise role of PAR2 on neuro-immune communication in AD has been hampered by the lack of appropriate animal models.Methods: We used a recently established mouse model with epidermal overexpression of PAR2 (PAR2OE) and littermate WT mice to study the impact of increased PAR2 expression in epidermal cells on spontaneous and house dust mite (HDM)-induced skin inflammation, itch, and barrier dysfunction in AD, in vivo and ex vivo.Results: PAR2OE newborns displayed no overt abnormalities, but spontaneously developed dry skin, severe pruritus, and eczema. Dermatological, neurophysiological, and immunological analyses revealed the hallmarks of AD-like skin disease. Skin barrier defects were observed before onset of skin lesions. Application of HDM onto PAR2OE mice triggered pruritus and the skin phenotype. PAR2OE mice displayed an increased density of nerve fibers, increased nerve growth factor and endothelin-1 expression levels, alloknesis, enhanced scratching (hyperknesis), and responses of dorsal root ganglion cells to non-histaminergic pruritogens.Conclusion: PAR2 in keratinocytes, activated by exogenous and endogenous proteases, is sufficient to drive barrier dysfunction, inflammation, and pruritus and sensitize skin to the effects of HDM in a mouse model that mimics human AD. PAR2 signaling in keratinocytes appears to be sufficient to drive several levels of neuro-epidermal communication, another feature of human AD.
Highlights
Protease-activated receptors (PARs) constitute a family of G protein-coupled receptors activated by proteolytic cleavage of their extracellular N-termini
We utilized Grhl3Par2/+ mice in which the mouse Par2 coding sequence, an internal ribosomal entry site and beta-galactosidase gene were inserted at the start codon of the grainyhead-like3 (Grhl3) gene (Grhl3PAR2/+) by homologous recombination [6]
PAR2 in keratinocytes (PAR2OE) mice were born without any overt abnormalities, they started to develop eczematous skin lesions spontaneously after several weeks of life
Summary
Protease-activated receptors (PARs) constitute a family of G protein-coupled receptors activated by proteolytic cleavage of their extracellular N-termini. Possible roles for PAR2 in inflammation and neuro-immune communication in various organs have been described [4,5,6,7,8,9,10,11,12,13]. Recent studies indicate an important function of PAR2 in atopic dermatitis (AD) and Netherton syndrome. This latter condition is a rare genetic disease caused by mutations in SPINK5, encoding the key serine protease inhibitor LEKTI in the epidermis leading to AD-like skin symptoms [22]. Activation of protease-activated receptor-2 (PAR2) has been implicated in inflammation, pruritus, and skin barrier regulation, all characteristics of atopic dermatitis (AD), as well as Netherton syndrome which has similar characteristics. Understanding the precise role of PAR2 on neuro-immune communication in AD has been hampered by the lack of appropriate animal models
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