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

Int J Mol Sci. 2020 Jul 29;21(15):5382. 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.

Keywords: IL-13; IL-17A; IL-22; IL-4; atopic dermatitis; filaggrin; filaggrin-2; involucrin; loricrin; skin barrier.

Publication types

  • Review

MeSH terms

  • Antioxidants / therapeutic use
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / immunology
  • Coal Tar / therapeutic use
  • Dermatitis, Atopic / drug therapy
  • Dermatitis, Atopic / genetics*
  • Dermatitis, Atopic / immunology
  • Dermatitis, Atopic / pathology
  • Filaggrin Proteins
  • 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
  • Membrane Proteins / genetics*
  • Membrane Proteins / immunology
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / immunology
  • Oxidative Stress
  • Protein Precursors / genetics*
  • Protein Precursors / immunology
  • Receptors, Aryl Hydrocarbon / genetics*
  • Receptors, Aryl Hydrocarbon / immunology
  • Resorcinols / therapeutic use
  • S100 Proteins / genetics*
  • S100 Proteins / immunology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology
  • STAT6 Transcription Factor / genetics
  • STAT6 Transcription Factor / immunology
  • Signal Transduction
  • Skin / drug effects
  • Skin / immunology
  • Skin / pathology
  • Stilbenes / therapeutic use
  • Tars / therapeutic use

Substances

  • AHR protein, human
  • Antioxidants
  • Basic Helix-Loop-Helix Transcription Factors
  • FLG protein, human
  • FLG2 protein, human
  • Filaggrin Proteins
  • IL17A protein, human
  • IL4 protein, human
  • Interleukin-13
  • Interleukin-17
  • Interleukins
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Protein Precursors
  • Receptors, Aryl Hydrocarbon
  • Resorcinols
  • S100 Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Stilbenes
  • Tars
  • loricrin
  • Interleukin-4
  • glyteen
  • involucrin
  • Coal Tar
  • tapinarof