Protease-Activated Receptor-2 Regulates Neuro-Epidermal Communication in Atopic Dermatitis

Area of Science:

• Immunology
• Dermatology
• Neuroscience

Background:

• Protease-activated receptor-2 (PAR2) is linked to inflammation and itch in atopic dermatitis (AD).
• A lack of suitable animal models has limited understanding of PAR2's role in AD neuro-immune communication.

Purpose of the Study:

• To investigate the impact of epidermal PAR2 overexpression on AD-like skin inflammation, itch, and barrier dysfunction.
• To utilize a novel PAR2-overexpressing (PAR2OE) mouse model for in vivo and ex vivo studies.

Main Methods:

• Comparison of PAR2OE mice with wild-type (WT) littermates.
• Assessment of spontaneous and house dust mite (HDM)-induced skin inflammation, pruritus, and barrier function.
• Dermatological, neurophysiological, and immunological analyses.

Main Results:

• PAR2OE mice spontaneously developed AD-like dry skin, severe pruritus, and eczema with pre-existing skin barrier defects.
• HDM exposure exacerbated pruritus and skin phenotype in PAR2OE mice.
• Increased nerve fiber density, elevated nerve growth factor and endothelin-1, alloknesis, hyperknesis, and altered dorsal root ganglion cell responses were observed.

Conclusions:

• PAR2 activation in keratinocytes is sufficient to induce skin barrier dysfunction, inflammation, and pruritus.
• PAR2 signaling in keratinocytes drives neuro-epidermal communication, mimicking key aspects of human AD.
• The PAR2OE mouse model effectively mimics human AD, enabling further study of PAR2's role.