Journal Article

Regulation of Filaggrin, Loricrin, and Involucrin by IL-4, IL-13, IL-17A, IL-22, AHR, and NRF2: Pathogenic Implications in Atopic Dermatitis

Furue, Masutaka

2020

Overview

Atopic dermatitis (AD) is an eczematous, pruritic skin disorder with extensive barrier dysfunction and elevated interleukin (IL)-4 and IL-13 signatures. The barrier dysfunction correlates with the downregulation of barrier-related molecules such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL). IL-4 and IL-13 potently inhibit the expression of these molecules by activating signal transducer and activator of transcription (STAT)6 and STAT3. In addition to IL-4 and IL-13, IL-22 and IL-17A are probably involved in the barrier dysfunction by inhibiting the expression of these barrier-related molecules. In contrast, natural or medicinal ligands for aryl hydrocarbon receptor (AHR) are potent upregulators of FLG, LOR, and IVL expression. As IL-4, IL-13, IL-22, and IL-17A are all capable of inducing oxidative stress, antioxidative AHR agonists such as coal tar, glyteer, and tapinarof exert particular therapeutic efficacy for AD. These antioxidative AHR ligands are known to activate an antioxidative transcription factor, nuclear factor E2-related factor 2 (NRF2). This article focuses on the mechanisms by which FLG, LOR, and IVL expression is regulated by IL-4, IL-13, IL-22, and IL-17A. The author also summarizes how AHR and NRF2 dual activators exert their beneficial effects in the treatment of AD.

• Publisher: MDPI AG,MDPI
• Subject: Amino acids / Antioxidants - therapeutic use / Basic Helix-Loop-Helix Transcription Factors - genetics / Basic Helix-Loop-Helix Transcription Factors - immunology / Cell adhesion & migration / Coal Tar - therapeutic use / Cytokines / Dermatitis / Dermatitis, Atopic - drug therapy / Dermatitis, Atopic - genetics / Dermatitis, Atopic - immunology / Dermatitis, Atopic - pathology / Eczema / Filaggrin Proteins / Gene expression / Gene Expression Regulation / Humans / Interleukin-13 - genetics / Interleukin-13 - immunology / Interleukin-17 - genetics / Interleukin-17 - immunology / Interleukin-22 / Interleukin-4 - genetics / Interleukin-4 - immunology / Interleukins - genetics / Interleukins - immunology / Keratin / Kinases / Lipids / Membrane Proteins - genetics / Membrane Proteins - immunology / Mutation / NF-E2-Related Factor 2 - genetics / NF-E2-Related Factor 2 - immunology / Oxidative Stress / Pollutants / Protein Precursors - genetics / Protein Precursors - immunology / Proteins / Psoriasis / Receptors, Aryl Hydrocarbon - genetics / Receptors, Aryl Hydrocarbon - immunology / Resorcinols - therapeutic use / Review / S100 Proteins - genetics / S100 Proteins - immunology / Signal Transduction / Skin / Skin - drug effects / Skin - immunology / Skin - pathology / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - immunology / STAT6 Transcription Factor - genetics / STAT6 Transcription Factor - immunology / Sterols / Stilbenes - therapeutic use / Tars - therapeutic use