Antagonistic antibodies used to establish the key role for IL-13 signaling via the type 2 IL-4 receptor in experimental atopic dermatitis

Almog Bitton ¹ Hadar Reichman ² Michal Itan ² Danielle Karo-Atar ² Perri Rozenberg ² Yael Diesendruck ¹ Limor Nahary ¹ Ariel Munitz ² Itai Benhar ¹

¹School of Molecular Cell Biology and Biotechnology, the George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel
²Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Israel

Background: IL-13 and IL-4 are potent mediators of type 2-associated inflammation such as those found in asthma and atopic dermatitis (AD). IL-4 shares overlapping biological functions with IL-13, a finding that is mainly explained by their ability to signal via the type 2 IL-4 receptor, which is comprised of IL-4Ra in association with IL-13Ra1. Nonetheless, the role of the type 2 IL-4R in AD remains to be defined.

Objective: To analyze the role of the type 2 IL-4R in experimental AD and assess its potential as a therapeutic target.

Methods: WT and Il13ra1^-/- mice were treated with oxazolone and with neutralizing anti-IL-4 antibodies. Thereafter, ear thickness, histopathology, cytokine and chemokine expression and cellular infiltrate were determined. Anti-mouse and –human IL-13Ra1 antibodies were generated and their ability to neutralize the type 2 IL-4R was assessed in vitro and in vivo.

Results: Oxazolone-induced dermatitis was dependent on the type 2 IL-4R. Expression of oxazolone-induced CCL11, CCL17, CXCL1 and CCL2 were dependent on the type 2 IL-4R, whereas CCL24 expression and eosinophilia were type 2 IL-4R-independent. Expression of CCL11, CXCL1, CCL17 and CCL2 was mediated by IL-13 signaling via the type 2 IL-4R, while CCL24 and eosinophilia were dependent on IL-4 signaling via the type 1 IL-4R. Pharmacological targeting of the type 2 IL-4R was capable of alleviating oxazolone-induced AD.

Conclusions: We demonstrate a critical role for IL-13 signaling through the type 2 IL-4R in AD. Furthermore, our data suggest that targeting the type 2 IL-4R may be beneficial for treatment of AD.