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

Masutaka Furue

doi:10.3390/ijms21155382

Abstract

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.

Highlights

The human epidermis is composed of stratified layers, differentiating from the basal layer on the basement membrane, towards spinous and granular layers, and to the outermost cornified layer [1,2,3,4,5,6]
Was canceled in keratinocytes treated with STAT6 small interfering RNA (siRNA), but not in those with STAT3 siRNA [127]. These results indicate that the IL-4/IL-13-mediated activation of STAT3 transmits signals different from
These results indicate that the IL-4/IL-13-mediated activation of STAT3 transmits signals different from those by the IL-4/IL-13-mediated activation of STAT6, and that IL-4/IL-13-mediated STAT3 activation is probably responsible for the downregulation of epidermal differentiation complex (EDC) molecules in keratinocytes [127]

Summary

Introduction

The human epidermis is composed of stratified layers, differentiating from the basal layer on the basement membrane, towards spinous and granular layers, and to the outermost cornified layer [1,2,3,4,5,6]. The cornified cells provide a specialized cell membrane called the cornified and barrier-related molecules, including K1, K10, desmosomal proteins (envoplakin and periplakin), envelope. The cornified envelope is composed of various cytoskeletal and barrier-related molecules, LOR, FLG, filaggrin-2 (FLG2), and involucrin (IVL), which are crosslinked by transglutaminase 1 and including K1, K10, desmosomal proteins (envoplakin and periplakin), LOR, FLG, filaggrin-2 (FLG2), partly by transglutaminases 3 and 5 [1,2,3,4,5,6]. Cornified envelope formation starts from desmosomes where IVL is crosslinked with envoplakin, periplakin, and keratin filaments by transglutaminase 1 [5,6] This protein complex becomes the scaffold for the corneocyte-bound lipid envelope [6,10]. [5,64,65,66]

Upregulation

IL-4IL-4

Findings

Conclusions