Dr. Fernández-Fernández and Dr. Sesma reply

Abstract

While playing an important role in host defense against extracellular pathogens, the IL-23/IL-17 axis is inherently linked to autoimmune disease. Biologic therapies have been developed that target the p19 subunit of IL-23 and IL-17A or IL-17R; and show remarkable efficacy against a range of autoimmune conditions including Psoriasis (PsO). Despite this clinical validation, the cellular pathways induced by IL-23 remain poorly defined. In order to better understand the role of RORγt in this pathway, we administered a potent and selective inhibitor of RORγt in a model of IL-23 mediated skin inflammation, which closely models human PsO. Looking specifically at skin, to differentiate from previous studies, we show that the accumulation of RORγt expressing cells is an early event following exogenous IL-23 exposure. Expansion of these RORγt expressing cells paralleled disease progression (inflammation) with both αβ and γδ T cells contributing to this population. Inhibition of RORγt with a novel small molecule inverse agonist significantly attenuated ear inflammation and histological endpoints related to human PsO. Furthermore, use of this compound attenuated both the accumulation of RORγt positive cells and their effector function (IL-17A production). Finally, inhibition of RORγt had profound downstream consequences, leading to significant recovery of keratinocyte dysregulation and normalization of anti-microbial gene expression. Collectively our studies confirm that RORγt expressing cells are an early feature of IL-23 mediated skin inflammation, reside predominantly in the T cell compartment, and play an active role in keratinocyte biology and disease pathology.