Neutralizing IL-22RA1 improves histologic and molecular alterations associated with atopic dermatitis pathogenesis.

Abstract

BACKGROUND: Disease of a subgroup of patients with atopic dermatitis (AD) does not show sufficient improvement with current systemic therapies, highlighting the heterogeneity of the chronic inflammatory skin disease and the need for novel treatments. OBJECTIVE: In this study, we investigated the pathogenic contribution of the IL-22/IL-22 receptor (IL-22RA1) axis to AD skin inflammation in in vitro, ex vivo, and in vivo models to evaluate the therapeutic potential of blocking this axis. METHODS: IL22RA1 expression in AD skin was assessed by in situ hybridization. Inhibition of the IL-22/IL-22R signaling cascade was evaluated in a human AD in vitro model (3-D skin equivalents) and a phorbol 12-myristate 13-acetate (aka TPA) mouse model using temtokibart, a humanized antibody directed against IL-22RA1. RESULTS: IL22RA1 was highly expressed in the epidermis of lesional AD skin versus nonlesional control skin; expression correlated positively with epidermal thickness and negatively with the barrier integrity marker loricrin. IL-22 stimulation in 3-D skin equivalents induced a specific molecular signature associated with lack of terminal differentiation, altered lipid metabolism, and increased immune response. Inhibition of IL-22RA1 with temtokibart showed significant improvements in skin barrier integrity at the histologic and molecular levels. IL-22RA1 inhibition in a skin inflammation mouse model with Zymo, a surrogate murine anti-IL-22RA1 monoclonal antibody for temtokibart, reduced local expression of Cxcl1 and S100a9. CONCLUSIONS: These findings suggest that the IL-22/IL-22RA1 axis functionally contributes to AD pathogenesis. Thus, blocking IL-22RA1 represents a potentially valuable new therapeutic option.