From Bench to Clinic: the Potential of Therapeutic Targeting of the IL-22 Signaling Pathway in Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is the most common pruritic inflammatory skin disease characterized by thickening of epidermis and dermis as well as by the infiltration of multiple pathogenic polarized T lymphocytes, including Th2, Th17, and Th22 cells. Significant progress has been made to develop targeted therapeutics for treating AD, e.g., Food and Drug Administration-approved dupilumab, an antibody for dual targeting of IL-4 and IL-13 signaling pathways. Additionally, a growing body of published evidence and a promising result from the early stage of the clinical trial with ILV-094, an anti-IL-22 antibody, strongly support the notion that IL-22 is a potential therapeutic target for treating AD. Moreover, we also experimentally proved that IL-22 contributes to the pathophysiology of AD by employing a murine model of AD induced by epicutaneous sensitization. Here, we review recent preclinical and clinical findings that have advanced our understanding of the roles of IL-22 and Th22 cells in skin inflammation. We conclude that blockade of IL-22 signaling may be a promising therapeutic approach for the treatment of AD.

Keywords: Atopic dermatitis; IL-22; Th22.

Figure 1. Potential therapeutic targeting of Th22/IL-22 signaling pathways in AD. Skin barrier defects caused by scratching or genetic mutations lead to penetration of external antigens and keratinocyte production of IL-23 via endogenous TLR4 ligand/TLR4 axis. A subset of IL-23R expressing DCs are activated and triggers AHR dependent Th22 immune response. Skin infiltrated CCR6⁺ Th22 cells induce epidermal hyperplasia and barrier dysfunction via IL-22/IL-22R signaling axis. Targeting TLR4/IL-23/Th22/IL-22 as well as CCL20/CCR6 pathways might be a promising strategy to overcome atopic skin inflammation.