Ann Dermatol.  2019 Apr;31(2):186-195. 10.5021/ad.2019.31.2.186.

Adiponectin Attenuates the Inflammation in Atopic Dermatitis-Like Reconstructed Human Epidermis

• Seo HS
• Seong KH
• Kim CD
• Seo SJ
• Park BC
• Kim MH
• Hong SP

• KMID: 2439064
• DOI: http://doi.org/10.5021/ad.2019.31.2.186

Abstract

BACKGROUND
Atopic dermatitis (AD) is a chronic disorder, with a vicious cycle of repetitive inflammation and deterioration of the epidermal barrier function. Adiponectin, an adipokine, has anti-inflammatory effects on various metabolic and inflammatory disorders. Recently, its level was found to be reduced in serum and tissue samples from AD patients.
OBJECTIVE
We aimed to investigate the effects of adiponectin on epidermal inflammation and barrier structures in AD skin.
METHODS
A three-dimensional in vitro epidermal equivalent model mimicking AD was obtained by adding an inflammatory substance cocktail to normal human epidermal equivalents (HEEs). The expression of epidermal differentiation markers, primary inflammatory mediators, and lipid biosynthetic enzymes was compared between adiponectintreated AD-HEEs, untreated control AD-HEEs, and normal HEEs.
RESULTS
Adiponectin co-treatment 1) inhibited the increase in mRNA expression of major inflammatory mediators (carbonic anhydrase II, neuron-specific NEL-like protein 2, thymic stromal lymphopoietin, interleukin-8, tumor necrosis factor-alpha, and human beta-defensin-2) from keratinocytes in AD-inflammatory HEEs, 2) enhanced the expression of lipid biosynthetic enzymes (fatty acid synthase, HMG CoA reductase, and serine-palmitoyl transferase), and 3) promoted the expression of differentiation factors, especially filaggrin. We also found that the expression of adiponectin receptor-1 and -2 decreased in the epidermis of chronic AD lesion.
CONCLUSION
Activation of the adiponectin pathway is expected to enhance epidermal differentiation and barrier function as well as attenuate inflammatory response to AD as a therapeutic approach.

Keyword

Adiponectin; Atopic dermatitis; Epidermal barrier; Keratinocyte; Lipid synthesis

MeSH Terms

Adipokines
Adiponectin*
Antigens, Differentiation
Dermatitis, Atopic
Epidermis*
Humans*
Hydroxymethylglutaryl CoA Reductases
In Vitro Techniques
Inflammation*
Interleukin-8
Keratinocytes
RNA, Messenger
Skin
Tumor Necrosis Factor-alpha
Adipokines
Adiponectin
Antigens, Differentiation
Hydroxymethylglutaryl CoA Reductases
Interleukin-8
RNA, Messenger
Tumor Necrosis Factor-alpha

Figure

• 

  Fig. 1 Schedule to develop in vitro cultured human epidermal equivalents (HEEs) model mimicking atopic dermatitis (AD). During the preparation of reconstructed three-dimensional epidermis, the cocktail containing Poly(I:C) and inflammatory cytokines was treated on the 11th day after air-lift to generate AD-HEEs. Adiponectin was co-treated with the cocktail at the same time to investigate the effect of adiponectin on AD conditioned epidermis. And then the samples were harvested for analysis 3 days later. Tx.: treatment, TLR: Toll-like receptor 3, TNF-α: tumor necrosis factor-alpha, IL: interleukin.

• 

  Fig. 2 Immunohistochemical staining of normal skin and atopic dermatitis lesional skin for adiponectin receptors. Protein expression of (A) adiponectin receptor-1 (AdipoR1) and (B) -2 (AdipoR2) in human epidermis were diminished in 3 atopic dermatitis patients, compared to control epidermis from 3 normal young adults (n=3 in each group). Bar=100 µm.

• 

  Fig. 3 Effects of adiponectin on inflammatory markers in three-dimensional skin atopic dermatitis (AD) model. The quantitative real-time reverse transcriptase polymerase chain reaction analysis showed the changes in the expression of major inflammatory markers by adiponectin treatment. (A) carbonic anhydrase II (CAII), (B) neuron-specific NEL-like protein 2 (NELL2), (C) thymic stromal lymphopoietin (TSLP) were evaluated as the specific inflammatory markers for atopic dermatitis. Others, (D) human beta-defensin 2 (hBD2), (E) interleukin (IL)-8, and (F) tumor necrosis factor-alpha (TNF-α) were assessed as the primary inflammatory markers. *p<0.05, **p<0.01.

• 

  Fig. 4 Representative microscopic finding of (A) normal untreated control, (B) control for reconstructed epidermal atopic dermatitis (AD) model (only the inflammatory cocktail treated), and (C) the adiponectin treated sample (the inflammatory cocktail and adiponectin co-treated). HEEs: human epidermal equivalents, Tx.: treatment.

• 

  Fig. 5 Effects of adiponectin on expression of lipid synthesis related gene in atopic dermatitis reconstructed epidermal model. By using the quantitative real-time reverse transcriptase polymerase chain reaction analysis, major rate-limiting epidermal lipid biosynthesis enzymes (A) fatty acid synthase, (B) HMG CoA reductase, and (C) serine palimitoyl transferase, and the transcription factors encoding for lipid synthesis enzymes (D) sterol regulatory binding protein 1a (SREBP1a), (E) SREBP1c, and (F) SREBP2 were assessed. *p<0.05, **p<0.01.

• 

  Fig. 6 Effects of adiponectin on epidermal differentiation in atopic dermatitis (AD) reconstructed epidermal model. The mRNA expression of the major epidermal differentiation markers (A) filaggrin (FLG), (B) loricrin, and (C) involucrin was quantified using real time reverse transcriptase polymerase chain reaction. (D) Representative immunohistochemical staining of untreated normal epidermal equivalent (normal-HEEs), and AD mimicking epidermis equivalent (AD-HEEs), and adiponectin treated AD mimicking equivalent (AD-HEEs+adiponectin) with human filaggrin antibody. Tx.: treatment. Bar=50 µm. *p<0.05, **p<0.01.

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