IL-17C drives skin inflammation in calcipotriol-induced rodent model of atopic dermatitis

Interleukin-17C (IL-17C) is a distinct member of the IL-17-family that was shown to play a role in psoriasis. The potential role of IL-17C in other inflammatory skin diseases, like atopic dermatitis (AD) remained to be elucidated. To clarify this, we evaluated IL-17C expression in human AD skin and evaluated anti-IL17C antibody MOR106 in a mouse model of AD.

Materials & Methods:
Expression of IL-17C in biopsies from atopic dermatitis patients was examined by immunohistochemistry. The effect of MOR106 was evaluated in the calcipotriol-induced cutaneous inflammation model of atopic dermatitis. Skin lesions were induced in Balb/c mice by topical administration of calcipotriol on both ears for 5 consecutive days and mice were sacrificed at day 8. MOR106 was administered intraperitoneally 3 days before, at start and 4 days after the first application of calcipotriol. Ear swelling was evaluated daily using a thickness gage and ear inflammation was assessed on day 5 by in vivo imaging 24hr after injection of a cathepsin-sensitive probe. At end of study, ears were collected and sections were stained with hematoxylin and eosin for histomorphometric evaluation of epidermal and dermal thickness. Parts of the ears were processed to analyze expression of several AD-related genes by qPCR and/or protein levels by ELISA. Serum was collected to analyze expression of TARC.

Results:
In the skin of atopic dermatitis patients, expression of IL-17C was higher than in healthy skin. Treatment of mice with MOR106 attenuated the ear swelling induced upon application of calcipotriol. Consistently, histomorphometric analysis of skin demonstrated a reduction of acanthosis in MOR106-treated animals and ear inflammation was reduced as well. TSLP and IL33 protein expression in ears and TARC levels in plasma were increased in calcipotriol-treated mice and significantly inhibited by treatment with MOR106. A similar inhibitory effect was observed on several other AD relevant genes (qPCR measurement), which were increased in the ears by calcipotriol, like IL4, IFNg and S100A8/9.

Conclusions:
Our data strongly suggest that IL-17C may play an important pro-inflammatory role in AD. Inhibiting its activity with the mAb MOR106 might be a potential novel therapeutic paradigm for treating AD.

Authors

Nick Vandeghinste (1)
Jürgen Klattig (2
Marielle Auberval (3)
Catherine Jagerschmidt (3)
Stéphanie Lavazais (3)
Florence Marsais (3)
Maarten Van Balen (1)
Philippe Clement-Lacroix (3)
Sonia Dupont (3)
Liên Lepescheux (3)
Jan Haas (2)
Stefan Härtle (2)
Stefan Steidl (2)
Juha Lindner (2)
Johan Beetens (1)
Reginald Brys (1)

Organisations

Galapagos NV, Generaal De Wittelaan L11A3, 2800 Mechelen, Belgium (1)
MorphoSys AG, Semmelweisstra╬▓e 7, 82152 Planegg, Germany (2)
Galapagos SaSu, 102 Avenue Gaston Roussel, 93230 Romainville, France (3)

Presenting author

Nick Vandeghinste, Senior Therapeutic Area Lead, Galapagos NV
nick.vandeghinste@glpg.com
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