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.

Keratinocytes: innate immune cells in atopic dermatitis

“…Th2 cytokines are predominant in the acute phase of AD, but IL‐22 was implicated in the chronic phase of AD when the epidermis becomes thickened due to the hyperplasia of keratinocytes (acanthosis) [1,70]. IL‐22 is a member of the IL‐10 cytokine family and is secreted by different types of T cells, including Th17 and Th22 cells [93]. Pronounced infiltration of Th22 cells and increased expression of IL‐22 in skin lesions of patients with AD have been reported [93,94].…”

“…IL‐22 is a member of the IL‐10 cytokine family and is secreted by different types of T cells, including Th17 and Th22 cells [93]. Pronounced infiltration of Th22 cells and increased expression of IL‐22 in skin lesions of patients with AD have been reported [93,94]. IL‐22 has multiple effects on keratinocytes, including the promotion of keratinocyte proliferation and migration via signal transducer and activator of transcription (STAT)‐3 phosphorylation, which is downstream of the IL‐22 receptor in keratinocytes [95].…”

Immunological Aspects of Skin Aging in Atopic Dermatitis

“…In addition to the strong Th2 immune response driving an increased level of Th2 cytokines and chemokines (IL-4, IL-5, IL-13, IL-31, and CCL18) [132], the Th22 response (IL-22 and S100A proteins) is also characteristic for the acute AD lesions in adults [133,134]. As a result of scratching due to itching, the endogeneous TLR-4 ligands stimulate the production of IL-23 from keratinocytes [135]. IL-23 further activates IL-23R expressing DCs, which trigger an aryl-hydrocarbon receptor (AHR)-dependent Th22 immune response [136].…”

“…IL-23 further activates IL-23R expressing DCs, which trigger an aryl-hydrocarbon receptor (AHR)-dependent Th22 immune response [136]. The activation of AHR stimulates a robust IL-22 expression on the affected keratinocytes in AD, implying a potential role of IL-22 as a promoter of epidermal hyperplasia and a contributor to the barrier defects [135,137]. The adult skin discloses an increased Th22 polarization, which presumably correlates with chronic immune stimulation over time.…”

Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation

“…Under hypoxia, even Th17 can produce IL-10 suggesting their immune regulatory function ( 52 ). In CD4 + T-cells, HIF-1α induces the production of IL-22 which is critical for barrier function in the gut mucosa via increasing proliferation of epithelial cells and expression of mucins and antimicrobial peptides ( 53 , 54 ). HIF-1α drives IL-10 expression in B-cells in controlling autoimmune inflammation such as arthritis and experimental autoimmune encephalomyelitis ( 55 ).…”