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Keratohyalin granules were discovered in the mid-19th century in cells that terminally differentiate to form the outer, cornified layer of the epidermis. The first indications of the composition of these structures emerged in the 1960s from a histochemical stain for histidine, followed by radioautographic evidence of a high incidence of histidine incorporation into newly synthesized proteins in cells containing the granules. Research during the next three decades revealed the structure and function of a major protein in these granules, which was initially called the ‘histidine-rich protein’. Steinert and Dale named the protein ‘filaggrin’ in 1981 because of its ability to aggregate keratin intermediate filaments. The human gene for the precursor, ‘profilaggrin,’ was reported in 1991 to encode 10, 11 or 12 nearly identical repeats. Remarkably, the mouse and rat genes encode up to 20 repeats. The lifetime of filaggrin is the time required for keratinocytes in the granular layer to move into the inner cornified layer. During this transition, filaggrin facilitates the collapse of corneocytes into ‘building blocks’ that become an impermeable surface barrier. The subsequent degradation of filaggrin is as remarkable as its synthesis, and the end-products aid in maintaining moisture in the cornified layer. It was apparent that ichthyosis vulgaris and atopic dermatitis were associated with the absence of this protein. McLean’s team in 2006 identified the cause of these diseases by discovering loss-of-function mutations in the profilaggrin gene, which led to dysfunction of the surface barrier. This story illustrates the complexity in maintaining a healthy, functional epidermis.

Filaggrin (FLG), an essential structural protein for skin barrier function, is downregulated under chronic inflammatory conditions, leading to disruption of the skin barrier. However, the detailed molecular mechanisms of how FLG changes in the context of chronic inflammation are poorly understood. Here, we identified the molecular mechanisms by which inflammatory cytokines inhibit FLG expression in the skin. We found that the AP1 response element within the −343/+25 of the FLG promoter was necessary for TNFα + IFNγ–induced down-regulation of FLG promoter activity. Using DNA affinity precipitation assay, we observed that AP1 subunit composition binding to the FLG promoter was altered from c-FOS:c-JUN (at the early time) to FRA1:c-JUN (at the late time) in response to TNFα + IFNγ stimulation. Knockdown of FRA1 or c-JUN abrogated TNFα + IFNγ–induced FLG suppression. Histone deacetylase (HDAC) 1 interacted with FRA1:c-JUN under TNFα + IFNγ stimulation. Knockdown of HDAC1 abrogated the inhibitory effect of TNFα + IFNγ on FLG expression. The altered expression of FLG, FRA1, c-JUN, and HDAC1 was confirmed in mouse models of 2,4-dinitrochlorobenzene–induced atopic dermatitis and imiquimod-induced psoriasis. Thus, the current study demonstrates that TNFα + IFNγ stimulation suppresses FLG expression by promoting the FRA1:c-JUN:HDAC1 complex. This study provides insight into future therapeutic strategies targeting the FRA1:c-JUN:HDAC1 complex to restore impaired FLG expression in chronic skin inflammation.

NKIRAS1 and NKIRAS2 (also called as κB-Ras) were identified as members of the atypical RAS family that suppress the transcription factor NF-κB. However, their function in carcinogenesis is still controversial. To clarify how NKIRAS acts on cellular transformation, we generated transgenic mice in which NKIRAS2 was forcibly expressed using a cytokeratin 15 (K15) promoter, which is mainly activated in follicle bulge cells. The ectopic expression of NKIRAS2 was mainly detected in follicle bulges of transgenic mice with NKIRAS2 but not in wild type mice. K15 promoter-driven expression of NKIRAS2 failed to affect the development of epidermis, which was evaluated using the expression of K10, K14, K15 and filaggrin. However, K15 promoter-driven expression of NKIRAS2 effectively suppressed the development of skin tumors induced by treatment with 7,12-dimethylbenz(a)anthracene (DMBA)/12- O -tetradecanoylphorbol 13-acetate (TPA). This observation suggested that NKIRAS seemed to function as a tumor suppressor in follicle bulges. However, in the case of oncogenic HRAS-driven cellular transformation of murine fibroblasts, knockdown of NKIRAS2 expression drastically suppressed HRAS-mutant-provoked cellular transformation, suggesting that NKIRAS2 was required for the cellular transformation of murine fibroblasts. Furthermore, moderate enforced expression of NKIRAS2 augmented oncogenic HRAS-provoked cellular transformation, whereas an excess NKIRAS2 expression converted its functional role into a tumor suppressive phenotype, suggesting that NKIRAS seemed to exhibit a biphasic bell-shaped enhancing effect on HRAS-mutant-provoked oncogenic activity. Taken together, the functional role of NKIRAS in carcinogenesis is most likely determined by not only cellular context but also its expression level.

Background and objectives: The purpose of this study was to confirm the effect of Galgeunhwanggeumhwangryeon-tang (GGRT) on the skin barrier integrity and inflammation in an atopic dermatitis-like animal model. Materials and Methods: The model was established using lipid barrier elimination (LBE) in BALB/c mice. Ceramide 3B, a control drug, and GGRT were applied to the skin of LBE mice. Gross observation and histological examination were combined with measurement of skin score, trans-epidermal water loss, and pH. The expression of filaggrin, kallikrein-related peptidase 7 (KLK7), protease-activated receptor-2 (PAR-2), thymic stromal lymphopoietin (TSLP), and interleukin 4 (IL-4) was examined. Results: The effect of GGRT on atopic dermatitis was estimated in silico using two individual gene sets of human atopic dermatitis. In animal experiments, GGRT treatment reduced atopic dermatitis-like symptoms, as confirmed via gross and histological observations, skin score, pH change, and trans-epidermal water loss. The expression level of filaggrin increased in the skin of GGRT-treated mice compared to that in the LBE group. The expression levels of KLK7, PAR2, TSLP, and IL-4 were decreased in GGRT-treated mice skin compared to those in LBE mice. Conclusions: We demonstrated that GGRT restored the skin barrier and reduced inflammatory reactions in a murine model of atopic dermatitis.

The discovery in 2006 that loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and can predispose to atopic dermatitis (AD) galvanized the dermatology research community and shed new light on a skin protein that was first identified in 1981. However, although outstanding work has uncovered several key functions of filaggrin in epidermal homeostasis, a comprehensive understanding of how filaggrin deficiency contributes to AD is still incomplete, including details of the upstream factors that lead to the reduced amounts of filaggrin, regardless of genotype. In this review, we re-evaluate data focusing on the roles of filaggrin in the epidermis, as well as in AD. Filaggrin is important for alignment of keratin intermediate filaments, control of keratinocyte shape, and maintenance of epidermal texture via production of water-retaining molecules. Moreover, filaggrin deficiency leads to cellular abnormalities in keratinocytes and induces subtle epidermal barrier impairment that is sufficient enough to facilitate the ingress of certain exogenous molecules into the epidermis. However, although FLG null mutations regulate skin moisture in non-lesional AD skin, filaggrin deficiency per se does not lead to the neutralization of skin surface pH or to excessive transepidermal water loss in atopic skin. Separating facts from chaff regarding the functions of filaggrin in the epidermis is necessary for the design efficacious therapies to treat dry and atopic skin.

A large body of literature is available on wound healing in humans. Nonetheless, a standardized ex vivo wound model without disruption of the dermal compartment has not been put forward with compelling justification. Here, we present a novel wound model based on application of negative pressure and its effects for epidermal regeneration and immune cell behaviour. Importantly, the basement membrane remained intact after blister roof removal and keratinocytes were absent in the wounded area. Upon six days of culture, the wound was covered with one to three-cell thick K14 + Ki67 + keratinocyte layers, indicating that proliferation and migration were involved in wound closure. After eight to twelve days, a multi-layered epidermis was formed expressing epidermal differentiation markers (K10, filaggrin, DSG-1, CDSN). Investigations about immune cell-specific manners revealed more T cells in the blister roof epidermis compared to normal epidermis. We identified several cell populations in blister roof epidermis and suction blister fluid that are absent in normal epidermis which correlated with their decrease in the dermis, indicating a dermal efflux upon negative pressure. Together, our model recapitulates the main features of epithelial wound regeneration, and can be applied for testing wound healing therapies and investigating underlying mechanisms.

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.

Mutations in the filaggrin gene are associated with a broad range of skin and allergic diseases. The biology of this molecule and the role of mutations in its altered function offer new insights into a range of conditions not previously thought to be related to one another. Mutations in the filaggrin gene ( FLG ) are among the most common and profound single-gene defects identified to date in the causation and modification of disease. FLG encodes an important epidermal protein abundantly expressed in the outer layers of the epidermis. 1 Approximately 10% of persons of European ancestry are heterozygous carriers of a loss-of-function mutation in FLG, resulting in a 50% reduction in expressed protein. 2 The critical role of filaggrin in epidermal function underlies the pathogenic importance of this gene in common dermatologic and allergic diseases. The spectrum of such diseases encompasses monogenic disorders of keratinization through complex abnormalities . . .

The aryl hydrocarbon receptor (AHR)/AHR-nuclear translocator (ARNT) system is a sensitive sensor for small molecular, xenobiotic chemicals of exogenous and endogenous origin, including dioxins, phytochemicals, microbial bioproducts, and tryptophan photoproducts. AHR/ARNT are abundantly expressed in the skin. Once activated, the AHR/ARNT axis strengthens skin barrier functions and accelerates epidermal terminal differentiation by upregulating filaggrin expression. In addition, AHR activation induces oxidative stress. However, some AHR ligands simultaneously activate the nuclear factor-erythroid 2-related factor-2 (NRF2) transcription factor, which is a master switch of antioxidative enzymes that neutralizes oxidative stress. The immunoregulatory system governing T-helper 17/22 (Th17/22) and T regulatory cells (Treg) is also regulated by the AHR system. Notably, AHR agonists, such as tapinarof, are currently used as therapeutic agents in psoriasis and atopic dermatitis. In this review, we summarize recent topics on AHR related to atopic dermatitis and psoriasis.

ObjectiveDisruption of the epithelial barrier plays an essential role in developing eosinophilic oesophagitis (EoE), a disease defined by type 2 helper T cell (Th2)-mediated food-associated and aeroallergen-associated chronic inflammation. Although an increased expression of interleukin (IL)-20 subfamily members, IL-19, IL-20 and IL-24, in Th2-mediated diseases has been reported, their function in EoE remains unknown.DesignCombining transcriptomic, proteomic and functional analyses, we studied the importance of the IL-20 subfamily for EoE using patient-derived oesophageal three-dimensional models and an EoE mouse model.ResultsPatients with active EoE have increased expression of IL-20 subfamily cytokines in the oesophagus and serum. In patient-derived oesophageal organoids stimulated with IL-20 cytokines, RNA sequencing and mass spectrometry revealed a downregulation of genes and proteins forming the cornified envelope, including filaggrins. On the contrary, abrogation of IL-20 subfamily signalling in Il20R2 −/− animals resulted in attenuated experimental EoE reflected by reduced eosinophil infiltration, lower Th2 cytokine expression and preserved expression of filaggrins in the oesophagus. Mechanistically, these observations were mediated by the mitogen-activated protein kinase (MAPK); extracellular-signal regulated kinases (ERK)1/2) pathway. Its blockade prevented epithelial barrier impairment in patient-derived air–liquid interface cultures stimulated with IL-20 cytokines and attenuated experimental EoE in mice.ConclusionOur findings reveal a previously unknown regulatory role of the IL-20 subfamily for oesophageal barrier function in the context of EoE. We propose that aberrant IL-20 subfamily signalling disturbs the oesophageal epithelial barrier integrity and promotes EoE development. Our study suggests that specific targeting of the IL-20 subfamily signalling pathway may present a novel strategy for the treatment of EoE.