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16 pages, 2314 KiB

Open AccessArticle

IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis

by Yen Hai Vu, Akiko Hashimoto-Hachiya, Masaki Takemura, Ayako Yumine, Yasutaka Mitamura, Takeshi Nakahara, Masutaka Furue and Gaku Tsuji

Int. J. Mol. Sci. 2020, 21(24), 9412; https://doi.org/10.3390/ijms21249412 - 10 Dec 2020

Cited by 28 | Viewed by 4196

Abstract

Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies [...] Read more.

Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors. Full article

(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis 2020)

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17 pages, 1122 KiB

Open AccessArticle

Changes in the Physicochemical Properties of Blood and Skin Cell Membranes as a Result of Psoriasis Vulgaris and Psoriatic Arthritis Development

by Izabela Dobrzyńska, Barbara Szachowicz-Petelska, Adam Wroński, Iwona Jarocka-Karpowicz and Elżbieta Skrzydlewska

Int. J. Mol. Sci. 2020, 21(23), 9129; https://doi.org/10.3390/ijms21239129 - 30 Nov 2020

Cited by 13 | Viewed by 2628

Abstract

Psoriasis is accompanied by disturbed redox homeostasis, with systemic and local oxidative stress promoting the modification of basic components of cellular membranes. Therefore, the aim of the study was to investigate the effect of development of psoriasis vulgaris and psoriatic arthritis on the [...] Read more.

Psoriasis is accompanied by disturbed redox homeostasis, with systemic and local oxidative stress promoting the modification of basic components of cellular membranes. Therefore, the aim of the study was to investigate the effect of development of psoriasis vulgaris and psoriatic arthritis on the composition and physicochemical properties of skin cell membranes (keratinocytes and fibroblasts) and blood cells (lymphocytes, granulocytes and erythrocytes). Both forms of psoriasis are characterized by decreased levels and changes in the localization of membrane phospholipids, and an increased level of sialic acid as well as the lipid peroxidation product (malondialdehyde), which resulted in an increase in the zeta potential of skin cells and blood cells, with granulocytes and lymphocytes affected more than erythrocytes. Using theoretical equations and the dependence of the cell membrane surface charge density as a function of pH, it was shown that patients with psoriatic arthritis have a greater increase in the concentration of negatively charged groups on the membrane surface and reduced the value of the association constant with H⁺ compared to patients with psoriasis vulgaris. Therefore, it can be suggested that the physicochemical parameters of membranes, skin and blood cells, especially lymphocytes, can be used to assess the severity of the disease. Full article

(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis 2020)

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15 pages, 3072 KiB

Open AccessArticle

TLR2 Deficiency Exacerbates Imiquimod-Induced Psoriasis-Like Skin Inflammation through Decrease in Regulatory T Cells and Impaired IL-10 Production

by Momoko Nakao, Makoto Sugaya, Hideki Fujita, Tomomitsu Miyagaki, Sohshi Morimura, Sayaka Shibata, Yoshihide Asano and Shinichi Sato

Int. J. Mol. Sci. 2020, 21(22), 8560; https://doi.org/10.3390/ijms21228560 - 13 Nov 2020

Cited by 10 | Viewed by 2914

Abstract

Emerging evidence has demonstrated that Toll-like receptors (TLRs) are associated with autoimmune diseases. In this study, we investigated the role of TLR2 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although TLR2 signaling is known to play a critical role in the induction of proinflammatory [...] Read more.

Emerging evidence has demonstrated that Toll-like receptors (TLRs) are associated with autoimmune diseases. In this study, we investigated the role of TLR2 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although TLR2 signaling is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, TLR2 deficiency unexpectedly exacerbated psoriasiform skin inflammation. Importantly, messenger RNA (mRNA) levels of Foxp-3 and IL-10 in the lesional skin were significantly decreased in TLR2 KO mice compared with wild-type mice. Furthermore, flow cytometric analysis of the lymph nodes revealed that the frequency of regulatory T cells (Tregs) among CD4-positive cells was decreased. Notably, stimulation with Pam3CSK4 (TLR2/1 ligand) or Pam2CSK4 (TLR2/6 ligand) increased IL-10 production from Tregs and DCs and the proliferation of Tregs. Finally, adoptive transfer of Tregs from wild-type mice reduced imiquimod-induced skin inflammation in TLR2 KO mice. Taken together, our results suggest that TLR2 signaling directly enhances Treg proliferation and IL-10 production by Tregs and DCs, suppressing imiquimod-induced psoriasis-like skin inflammation. Enhancement of TLR2 signaling may be a new therapeutic strategy for psoriasis. Full article

(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis 2020)

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14 pages, 4950 KiB

Open AccessArticle

CX3CR1 Deficiency Attenuates DNFB-Induced Contact Hypersensitivity through Skewed Polarization towards M2 Phenotype in Macrophages

by Sayaka Otobe, Teruyoshi Hisamoto, Tomomitsu Miyagaki, Sohshi Morimura, Hiraku Suga, Makoto Sugaya and Shinichi Sato

Int. J. Mol. Sci. 2020, 21(19), 7401; https://doi.org/10.3390/ijms21197401 - 07 Oct 2020

Cited by 6 | Viewed by 2905

Abstract

CX3CL1 can function as both an adhesion molecule and a chemokine for CX3CR1⁺ cells, such as T cells, monocytes, and NK cells. Recent studies have demonstrated that CX3CL1–CX3CR1 interaction is associated with the development of various inflammatory skin diseases. In this study, [...] Read more.

CX3CL1 can function as both an adhesion molecule and a chemokine for CX3CR1⁺ cells, such as T cells, monocytes, and NK cells. Recent studies have demonstrated that CX3CL1–CX3CR1 interaction is associated with the development of various inflammatory skin diseases. In this study, we examined CX3CR1 involvement in 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity using CX3CR1^−/− mice. Ear swelling and dermal edema were attenuated after DNFB challenge in CX3CR1^−/− mice. Expression of TNF-α, IL-6, and M1 macrophage markers was decreased in the ears of CX3CR1^−/− mice, whereas expression of M2 macrophage markers including arginase-1 was increased. Decreased TNF-α and IL-6 expression and increased arginase-1 expression were found in peritoneal macrophages from CX3CR1^−/− mice. Furthermore, ear swelling was attenuated by depleting dermal macrophages in wild-type mice to a similar level to CX3CR1^−/− mice. These results suggest that CX3CR1 deficiency could induce skewed polarization towards M2 phenotype in macrophages, resulting in attenuation of contact hypersensitivity response. Full article

(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis 2020)

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15 pages, 2840 KiB

Open AccessArticle

Cannabidiol Modifies the Formation of NETs in Neutrophils of Psoriatic Patients

by Piotr Wójcik, Marzena Garley, Adam Wroński, Ewa Jabłońska and Elżbieta Skrzydlewska

Int. J. Mol. Sci. 2020, 21(18), 6795; https://doi.org/10.3390/ijms21186795 - 16 Sep 2020

Cited by 19 | Viewed by 4517

Abstract

Psoriasis is associated with increased production of reactive oxygen species which leads to oxidative stress. As antioxidants can provide protection, the aim of this study was to evaluate the effects of cannabidiol (CBD) on neutrophil extracellular trap (NET) formation in psoriatic and healthy [...] Read more.

Psoriasis is associated with increased production of reactive oxygen species which leads to oxidative stress. As antioxidants can provide protection, the aim of this study was to evaluate the effects of cannabidiol (CBD) on neutrophil extracellular trap (NET) formation in psoriatic and healthy neutrophils. Important markers of NETosis were measured in healthy and psoriatic neutrophils after incubation with CBD, lipopolysaccharide (LPS), and LPS + CBD). The percentage of neutrophils undergoing NETosis and the level of NETosis markers (cfDNA, MPO, elastase) were higher in the neutrophils and blood plasma of psoriatic patients, compared to controls. After LPS treatment, all of the markers of NETosis, except elastase, and p47 and citrullinated histones, were increased in samples from healthy subjects and psoriasis patients. CBD reduced the concentrations of NETosis markers. This led to a reduction in NETosis, which was more pronounced in psoriatic neutrophils and neutrophils treated with LPS in both psoriatic and healthy participants. These results suggest that psoriatic patients neutrophils are at a higher risk of NETosis both in vitro and in vivo. CBD reduces NETosis, mainly in psoriatic neutrophils, possibly due to its antioxidant properties. The anti-NET properties of CBD suggest the positive effect of CBD in the treatment of autoimmune diseases. Full article

(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis 2020)

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17 pages, 2325 KiB

Open AccessArticle

Cannabidiol-Mediated Changes to the Phospholipid Profile of UVB-Irradiated Keratinocytes from Psoriatic Patients

by Wojciech Łuczaj, Izabela Dobrzyńska, Adam Wroński, M Rosário Domingues, Pedro Domingues and Elżbieta Skrzydlewska

Int. J. Mol. Sci. 2020, 21(18), 6592; https://doi.org/10.3390/ijms21186592 - 09 Sep 2020

Cited by 20 | Viewed by 3545

Abstract

UVB phototherapy is treatment for psoriasis, which increases phospholipid oxidative modifications in the cell membrane of the skin. Therefore, we carried out lipidomic analysis on the keratinocytes of healthy individuals and patients with psoriasis irradiated with UVB and treated with cannabidiol (CBD), phytocannabinoid [...] Read more.

UVB phototherapy is treatment for psoriasis, which increases phospholipid oxidative modifications in the cell membrane of the skin. Therefore, we carried out lipidomic analysis on the keratinocytes of healthy individuals and patients with psoriasis irradiated with UVB and treated with cannabidiol (CBD), phytocannabinoid with antioxidant and anti-inflammatory properties. Our results showed that, in psoriatic keratinocytes phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidylserine (PS), and ether-linked phosphoethanolamine (PEo), were downregulated, while SM (d41:2) was upregulated. These changes were accompanied by an increase in negative zeta potential, which indicates translocation of PS to the outer layer of the membrane. CBD treatment of psoriatic keratinocytes led to downregulation of PC, PS, and upregulation of certain PEo and an SM species, SM (d42:2), and the zeta potential. However, UVB irradiation of psoriatic keratinocytes resulted in upregulation of PC, PC plasmalogens (PCp), PEo, and a decrease in the negative zeta potential. The exposure of UVB-irradiated cells to CBD led to a decrease in the level of SM (d42:2). Our results suggest that CBD induces pro-apoptotic mechanisms in psoriatic keratinocytes while simultaneously improving the antioxidant properties and preventing the loss of transepidermal water of keratinocytes of patients irradiated with UVB. Thus, CBD has potential therapeutic value in the treatment of psoriasis. Full article

(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis 2020)

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22 pages, 6443 KiB

Open AccessArticle

Air Pollution and Atopic Dermatitis (AD): The Impact of Particulate Matter (PM₁₀) on an AD Mouse-Model

by Yu Ri Woo, Seo-Yeon Park, Keonwoo Choi, Eun Sun Hong, Sungjoo Kim and Hei Sung Kim

Int. J. Mol. Sci. 2020, 21(17), 6079; https://doi.org/10.3390/ijms21176079 - 24 Aug 2020

Cited by 22 | Viewed by 3578

Abstract

Air pollution reportedly contributes to the development and exacerbation of atopic dermatitis (AD). However, the exact mechanism underlying this remains unclear. To examine the relationship between air pollution and AD, a clinical, histological, and genetic analysis was performed on particulate matter (PM)-exposed mice. [...] Read more.

Air pollution reportedly contributes to the development and exacerbation of atopic dermatitis (AD). However, the exact mechanism underlying this remains unclear. To examine the relationship between air pollution and AD, a clinical, histological, and genetic analysis was performed on particulate matter (PM)-exposed mice. Five-week-old BALB/c mice were randomly divided into four groups (control group, ovalbumin (OVA) group, PM group, OVA + PM group; n = 6) and treated with OVA or PM_10, alone or together. Cutaneous exposure to OVA and PM₁₀ alone resulted in a significant increase in skin severity scores, trans-epidermal water loss (TEWL) and epidermal thickness compared to the control group at Week 6. The findings were further accentuated in the OVA + PM group showing statistical significance over the OVA group. A total of 635, 501, and 2149 genes were found to be differentially expressed following OVA, PM₁₀, and OVA + PM₁₀ exposure, respectively. Strongly upregulated genes included RNASE2A, S100A9, SPRR2D, THRSP, SPRR2A1 (OVA vs. control), SPRR2D, S100A9, STFA3, CHIL1, DBP, IL1B (PM vs. control) and S100A9, SPRR2D, SPRR2B, S100A8, SPRR2A3 (OVA + PM vs. control). In comparing the groups OVA + PM with OVA, 818 genes were differentially expressed with S100A9, SPRR2B, SAA3, S100A8, SPRR2D being the most highly upregulated in the OVA + PM group. Taken together, our study demonstrates that PM₁₀ exposure induces/aggravates skin inflammation via the differential expression of genes controlling skin barrier integrity and immune response. We provide evidence on the importance of public awareness in PM-associated skin inflammation. Vigilant attention should be paid to all individuals, especially to those with AD. Full article

(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis 2020)

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9 pages, 2228 KiB

Open AccessArticle

Skin Mycobiome of Psoriasis Patients is Retained during Treatment with TNF and IL-17 Inhibitors

by Yuta Koike, Sayaka Kuwatsuka, Katsutaro Nishimoto, Daisuke Motooka and Hiroyuki Murota

Int. J. Mol. Sci. 2020, 21(11), 3892; https://doi.org/10.3390/ijms21113892 - 29 May 2020

Cited by 10 | Viewed by 2904

Abstract

Background: Biological treatment relieves refractory skin lesions in patients with psoriasis; however, changes in the fungal microbiome (the mycobiome) on the skin are unclear. Methods: The skin mycobiome of psoriasis patients treated with TNF inhibitors (TNFi, n = 5) and IL-17 inhibitors (IL-17i, [...] Read more.

Background: Biological treatment relieves refractory skin lesions in patients with psoriasis; however, changes in the fungal microbiome (the mycobiome) on the skin are unclear. Methods: The skin mycobiome of psoriasis patients treated with TNF inhibitors (TNFi, n = 5) and IL-17 inhibitors (IL-17i, n = 7) was compared with that of patients not receiving systemic therapy (n = 7). Skin swab samples were collected from non-lesional post-auricular areas. Fungal DNA was sequenced by ITS1 metagenomic analysis and taxonomic classification was performed. Results: An average of 37543 reads/sample were analyzed and fungi belonging to 31 genera were detected. The genus Malassezia accounted for >90% of reads in 7/7 samples from the no-therapy group, 4/5 from the TNFi group, and 5/7 from the IL-17i group. Biodiversity was low in those three groups. Few members of the genus trichophyton were detected; the genus Candida was not detected at all. Among the Malassezia species, M. restricta was the major species in 6/7 samples from the no-therapy group, 4/5 from the TNFi group, and 5/7 from the IL-17i group whose the other largest species revealed M. globosa. Conclusions: The mycobiome is retained on post-auricular skin during systemic treatment with TNF and IL-17 inhibitors. Full article

(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis 2020)

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12 pages, 2041 KiB

Open AccessArticle

Exacerbated Imiquimod-Induced Psoriasis-Like Skin Inflammation in IRF5-Deficient Mice

by Momoko Nakao, Tomomitsu Miyagaki, Makoto Sugaya and Shinichi Sato

Int. J. Mol. Sci. 2020, 21(10), 3681; https://doi.org/10.3390/ijms21103681 - 23 May 2020

Cited by 3 | Viewed by 3745

Abstract

Interferon regulatory factors (IRFs) play diverse roles in the regulation of the innate and adaptive immune responses in various diseases. In psoriasis, IRF2 is known to be involved in pathogenesis, while studies on other IRFs are limited. In this study, we investigated the [...] Read more.

Interferon regulatory factors (IRFs) play diverse roles in the regulation of the innate and adaptive immune responses in various diseases. In psoriasis, IRF2 is known to be involved in pathogenesis, while studies on other IRFs are limited. In this study, we investigated the role of IRF5 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although IRF5 is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, IRF5 deficiency unexpectedly exacerbated psoriasiform skin inflammation. The interferon-α and tumor necrosis factor-α mRNA expression levels were decreased, while levels of Th17 cytokines including IL-17, IL-22, and IL-23 were increased in IRF5-deficient mice. Furthermore, IL-23 expression in DCs from IRF5-deficient mice was upregulated both in steady state and after toll-like receptor 7/8 agonist stimulation. Importantly, the expression of IRF4, which is also important for the IL-23 production in DCs, was augmented in DCs from IRF5-deficient mice. Taken together, our results suggest that IRF5 deficiency induces the upregulation of IRF4 in DCs followed by augmented IL-23 production, resulting in the amplification of Th17 responses and the exacerbation of imiquimod-induced psoriasis-like skin inflammation. The regulation of IRF4 or IRF5 expression may be a novel therapeutic approach to psoriasis. Full article

(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis 2020)

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13 pages, 2655 KiB

Open AccessArticle

Inflammatory Skin-Derived Cytokines Accelerate Osteoporosis in Mice with Persistent Skin Inflammation

by Kento Mizutani, Kana Isono, Yoshiaki Matsushima, Karin Okada, Ai Umaoka, Shohei Iida, Koji Habe, Kohei Hagimori, Hidetoshi Yamazaki and Keiichi Yamanaka

Int. J. Mol. Sci. 2020, 21(10), 3620; https://doi.org/10.3390/ijms21103620 - 20 May 2020

Cited by 19 | Viewed by 3379

Abstract

Secondary osteoporosis can also be caused by chronic inflammatory skin disease as well as rheumatoid arthritis or inflammatory bowel disease. However, the exact role of osteoporosis in inflammatory skin conditions has not been elucidated. Using a mouse model of dermatitis, we investigated the [...] Read more.

Secondary osteoporosis can also be caused by chronic inflammatory skin disease as well as rheumatoid arthritis or inflammatory bowel disease. However, the exact role of osteoporosis in inflammatory skin conditions has not been elucidated. Using a mouse model of dermatitis, we investigated the pathophysiology of osteoporosis in inflammatory skin conditions and the therapeutic impact of osteoporosis medication on inflammatory skin disease. We employed model mice of spontaneous skin inflammation, specifically overexpressing human caspase-1 in the epidermis. Bone density and the expression of various mRNAs in the femur were examined by micro CT and RT-PCR. The effects of minodronate and anti-RANKL antibody on bone structure, histology, and femur blood flow were studied. The mouse model of skin inflammation showed a marked decrease in bone density compared to wild-type littermates with abnormalities in both bone resorption and formation. Minodronate improved bone density by decreasing osteoclasts, but anti-RANKL antibody did not improve. In the dermatitis model, the blood flow in the bone marrow was decreased, and minodronate restored this parameter. A model of persistent dermatitis exhibited marked osteoporosis, but the impact of chronic dermatitis on osteoporosis has not been thoroughly investigated. We should explore the pathogenesis of osteoporosis in skin inflammatory diseases. Full article

(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis 2020)

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Review

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18 pages, 2114 KiB

Open AccessReview

Genetic and Epigenetic Aspects of Atopic Dermatitis

by Bogusław Nedoszytko, Edyta Reszka, Danuta Gutowska-Owsiak, Magdalena Trzeciak, Magdalena Lange, Justyna Jarczak, Marek Niedoszytko, Ewa Jablonska, Jan Romantowski, Dominik Strapagiel, Jarosław Skokowski, Anna Siekierzycka, Roman J. Nowicki, Iwona T. Dobrucki, Anna Zaryczańska and Leszek Kalinowski

Int. J. Mol. Sci. 2020, 21(18), 6484; https://doi.org/10.3390/ijms21186484 - 04 Sep 2020

Cited by 51 | Viewed by 6744

Abstract

Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also [...] Read more.

Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. Recent studies point to the key role of epigenetic changes in the development of the disease. Epigenetic modifications are mainly mediated by DNA methylation, histone acetylation, and the action of specific non-coding RNAs. It has been documented that the profile of epigenetic changes in patients with atopic dermatitis (AD) differs from that observed in healthy people. This applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting Th1 bias and promoting Th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. Understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies. Full article

(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis 2020)

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25 pages, 2575 KiB

Open AccessReview

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

by Masutaka Furue

Int. J. Mol. Sci. 2020, 21(15), 5382; https://doi.org/10.3390/ijms21155382 - 29 Jul 2020

Cited by 183 | Viewed by 13424

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis 2020)

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