Signaling In Keratinocytes Research Articles

Essential Role of STAT3 Signaling in Hair Follicle Homeostasis

Dominant-negative mutations associated with signal transducer and activator of transcription 3 (STAT3) signaling, which controls epithelial proliferation in various tissues, lead to atopic dermatitis in hyper IgE syndrome. This dermatitis is thought to be attributed to defects in STAT3 signaling in type 17 helper T cell specification. However, the role of STAT3 signaling in skin epithelial cells remains unclear. We found that STAT3 signaling in keratinocytes is required to maintain skin homeostasis by negatively controlling the expression of hair follicle-specific keratin genes. These expression patterns correlated with the onset of dermatitis, which was observed in specific pathogen-free conditions but not in germ-free conditions, suggesting the involvement of Toll-like receptor-mediated inflammatory responses. Thus, our study suggests that STAT3-dependent gene expression in keratinocytes plays a critical role in maintaining the homeostasis of skin, which is constantly exposed to microorganisms.

The GPI-anchored protein CD109 protects hematopoietic progenitor cells from undergoing erythroid differentiation induced by TGF-β.

Although a glycosylphosphatidylinositol-anchored protein (GPI-AP) CD109 serves as a TGF-β co-receptor and inhibits TGF-β signaling in keratinocytes, the role of CD109 on hematopoietic stem progenitor cells (HSPCs) remains unknown. We studied the effect of CD109 knockout (KO) or knockdown (KD) on TF-1, a myeloid leukemia cell line that expresses CD109, and primary human HSPCs. CD109-KO or KD TF-1 cells underwent erythroid differentiation in the presence of TGF-β. CD109 was more abundantly expressed in hematopoietic stem cells (HSCs) than in multipotent progenitors and HSPCs of human bone marrow (BM) and cord blood but was not detected in mouse HSCs. Erythroid differentiation was induced by TGF-β to a greater extent in CD109-KD cord blood or iPS cell-derived megakaryocyte-erythrocyte progenitor cells (MEPs) than in wild-type MEPs. When we analyzed the phenotype of peripheral blood MEPs of patients with paroxysmal nocturnal hemoglobinuria who had both GPI(+) and GPI(-) CD34+ cells, the CD36 expression was more evident in CD109- MEPs than CD109+ MEPs. In summary, CD109 suppresses TGF-β signaling in HSPCs, and the lack of CD109 may increase the sensitivity of PIGA-mutated HSPCs to TGF-β, thus leading to the preferential commitment of erythroid progenitor cells to mature red blood cells in immune-mediated BM failure.

Black Ginseng Extract Attenuates TNF-ɑ-Induced Inflammation via Downregulation of NF-κB Signaling in Human Keratinocytes

Won Yeoung Choi, Gye Won Lee, Deuk Sang Kwon, Hyun Joong Shin, and Young Ho Cho. Journal of the Korean Society of Food Science and Nutrition 2021;50:1030-9. https://doi.org/10.3746/jkfn.2021.50.10.1030

The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation.

Psoriasis is a chronic inflammatory skin disease associated with both innate and adaptive immune responses. The stimulator of interferon genes (STING) protein engages in sensing of cytosolic DNA to initiate dsDNA-driven immune responses. In vitro and in vivo anti-psoriasis effects of STING antagonist H-151 were explored. We analysed the gene expression profile of STING and related downstream targets in the skin samples of healthy people and psoriasis patients from the GEO database. Cellular inhibitory activity of H-151 on STING pathway was confirmed via qPCR and western blotting. The preventive effect of topical application of H-151 on imiquimod-induced psoriatic mice was examined through histological, immunohistochemical, immunofluorescent, flow cytometric analysis, ELISA Kits and other approaches. Preliminary mechanistic studies were also performed. Gene expressions of STING and its downstream target were up-regulated in lesional skin samples from psoriasis patients. Topical administration of H-151 attenuated the skin lesions in imiquimod-induced psoriatic mouse model, while the secretion of pro-inflammatory cytokines (IL-17, IL-23 and IL-6), infiltration of M1 macrophages and differentiation of Th17 cells were significantly suppressed by H-151 treatment. Mechanistically, H-151 inhibited STING/NF-κB signalling in both keratinocytes and immune cells. H-151 displayed anti-inflammatory activity in both keratinocytes and immune cells, and decreased the severity of psoriatic response in vivo. Inhibition of STING signalling pathway may represent a novel therapeutic approach to psoriasis and related complications.

OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice

Linear ubiquitination regulates inflammatory and cell death signalling. Deficiency of the linear ubiquitin chain-specific deubiquitinase, OTULIN, causes OTULIN-related autoinflammatory syndrome (ORAS), a systemic inflammatory pathology affecting multiple organs including the skin. Here we show that mice with epidermis-specific OTULIN deficiency (OTULINE-KO) develop inflammatory skin lesions that are driven by TNFR1 signalling in keratinocytes and require RIPK1 kinase activity. OTULINE-KO mice lacking RIPK3 or MLKL have only very mild skin inflammation, implicating necroptosis as an important etiological mediator. Moreover, combined loss of RIPK3 and FADD fully prevents skin lesion development, showing that apoptosis also contributes to skin inflammation in a redundant function with necroptosis. Finally, MyD88 deficiency suppresses skin lesion development in OTULINE-KO mice, suggesting that toll-like receptor and/or IL-1 signalling are involved in mediating skin inflammation. Thus, OTULIN maintains homeostasis and prevents inflammation in the skin by inhibiting TNFR1-mediated, RIPK1 kinase activity-dependent keratinocyte death and primarily necroptosis.

IL-6R/Signal Transducer and Activator of Transcription 3 Signaling in Keratinocytes rather than in T Cells Induces Psoriasis-Like Dermatitis in Mice

Signal transducer and activator of transcription 3 (STAT3) is important for psoriasis pathogenesis because STAT3 signaling downstream of IL-6, IL-21, IL-22, and IL-23 contributes to T helper type 17 cell development and because transgenic mice with keratinocyte (KC) STAT3 expression (K14-Stat3C mice) develop psoriasis-like dermatitis. In this study, the relative contribution of STAT3 signaling in KCs versus in T cells was evaluated in the imiquimod model of psoriasis-like dermatitis. Mice with STAT3-inducible deletion in KCs (K5-Stat3-/- mice) had decreased psoriasis-like dermatitis and epidermal STAT3 phosphorylation compared with wild-type mice, whereas mice with constitutive deletion of STAT3 in all T cells were similar to wild-type mice. Interestingly, mice with KC-inducible deletion of IL-6Rα had similar findings to those of K5-Stat3-/- mice, identifying IL-6/IL-6R as a predominant upstream signal for KC STAT3-induced psoriasis-like dermatitis. Moreover, psoriasis-like dermatitis inversely associated with type 1 immune gene products, especially CXCL10, whereas CXCL10 limited psoriasis-like dermatitis, suggesting that KC STAT3 signaling promoted psoriasis-like dermatitis by restricting downstream CXCL10 expression. Finally, treatment of mice with the pan-Jak inhibitor, tofacitinib, reduced psoriasis-like dermatitis and epidermal STAT3 phosphorylation. Taken together, STAT3 signaling in KCs rather than in T cells was a more important determinant for psoriasis-like dermatitis in a mechanism that involved upstream KC IL-6R signaling and downstream inhibition of type 1 immunity‒associated CXCL10 responses.

Keratinocytes Counteract UVB-Induced Immunosuppression in Mice through HIF-1a Signaling

The transcription factor HIF-1a regulates cellular metabolism under hypoxia but also immune responses and UVB-induced skin reactions. In keratinocytes (KCs), HIF-1a is an environmental sensor orchestrating the adaptation to environmental changes. In this study, we investigated the role of HIF-1a in KCs for skin reactions to acute and chronic UVB exposure in mice. The function of HIF-1a in KCs under UVB exposure was analyzed in KC-specific HIF-1a conditional knockout (cKO) mice. cKO mice were hypersensitive to acute high-dose UVB irradiation compared with wild-type mice, displaying increased cell death and delayed barrier repair. After chronic low-dose UVB treatment, cKO mice also had stronger epidermal damage but reduced infiltration of dermal macrophages and T helper cells compared with wild-type mice. Irradiated cKO mice revealed accumulation of regulatory lymphocytes in dorsal skin-draining lymph nodes compared with wild-type and unirradiated mice. This was reflected by an augmented IL-10 release of lymph node cells and a weaker contact hypersensitivity reaction to DNFB in UVB-exposed cKO mice than in wild-type and unirradiated controls. In summary, we found that KC-specific HIF-1a expression is crucial for adaptation to UVB exposure and inhibits the development of UVB-induced immunosuppression in mice. Therefore, HIF-1a signaling in KCs could ameliorate photoaging-related skin disorders.

Generalized Pustular Psoriasis: Divergence of Innate and Adaptive Immunity.

Generalized pustular psoriasis (GPP) is a severe, relapsing, immune-mediated disease characterized by the presence of multiple sterile pustules all over the body. The exact pathomechanisms behind GPP remain elusive, although increased interest in the genetic basis and immunological disturbances have provided some revealing insights into the underlying signaling pathways and their mutual interaction. The genetic background of GPP has been thoroughly investigated over the past few years. The conducted studies have identified genetic variants that predispose to pustular forms of psoriasis. The loss-of-function mutation of the interleukin 36 receptor antagonist gene, along with rare gain-of-function mutations in the gene that encodes the keratinocyte signaling molecule (CARD14), are examples of the uncovered abnormalities. Interleukin 36 (IL-36), along with neutrophils, is now considered a central cytokine in GPP pathogenesis, with IL-36 signaling providing a link between innate and adaptive immune responses. More recently, a new concept of inflammation, caused by a predominantly genetically determined abnormal activation of innate immune response and leading to inflammatory keratinization, has arisen. GPP is currently considered a representative of this novel group of skin conditions, called autoinflammatory keratinization diseases. As no therapeutic agents have been approved for GPP to date in the United States and Europe, the novel anti-IL-36R antibodies are particularly promising and may revolutionize management of the disease.

Guardians of the barrier: Microbiota engage AHR in keratinocytes to maintain skin homeostasis

The skin barrier is critical in ensuring homeostasis, yet factors influencing its development, repair, and maintenance are ill-defined. In this issue of Cell Host & Microbe, Uberoi etal. demonstrate the skin microbiota's role in maintaining barrier integrity via AHR signaling in keratinocytes, which has implications for skin disease management.

Solar Simulated Light Induces Cutaneous Squamous Cell Carcinoma in Inbred Mice: A Clinically Relevant Model to Investigate T-Cell Responses

More than one million cutaneous squamous cell carcinomas (cSCCs) are diagnosed annually in the United States (Rogers et al., 2015). The main causal factor of cSCC is UV exposure from sunlight, which is made of 95% UVA and 5% UVB at the Earth’s surface. UVA and UVB cause cyclobutane pyrimidine dimers in DNA and oxidative damage through the formation of ROS. The ratio of cyclobutane pyrimidine dimers to oxidative DNA damage products is ∼800 times greater in UVB than in UVA (Zhang et al., 1997). In addition, UVA and UVB have distinct effects on keratinocyte signaling pathways, including apoptosis (Bito et al., 2010; Syed et al., 2012).

Subversion of Lipopolysaccharide Signaling in Gingival Keratinocytes via MCPIP-1 Degradation as a Novel Pathogenic Strategy of Inflammophilic Pathobionts.

ABSTRACTPeriodontal disease (PD) is an inflammatory disease of the supporting tissues of the teeth that develops in response to formation of a dysbiotic biofilm on the subgingival tooth surface. Although exacerbated inflammation leads to alveolar bone destruction and may cause tooth loss, the molecular basis of PD initiation and progression remains elusive. Control over the inflammatory reaction and return to homeostasis can be efficiently restored by negative regulators of Toll-like receptor (TLR) signaling pathways such as monocyte chemoattractant protein-induced protein 1 (MCPIP-1), which is constitutively expressed in gingival keratinocytes and prevents hyperresponsiveness in the gingiva. Here, we found that inflammophilic periodontal species influence the stability of MCPIP-1, leading to an aggravated response of the epithelium to proinflammatory stimulation. Among enzymes secreted by periodontal species, gingipains—cysteine proteases from Porphyromonas gingivalis—are considered major contributors to the pathogenic potential of bacteria, strongly influencing the components of the innate and adaptive immune system. Gingipain proteolytic activity leads to a rapid degradation of MCPIP-1, exacerbating the inflammatory response induced by endotoxin. Collectively, these results establish a novel mechanism of corruption of inflammatory signaling by periodontal pathogens, indicating new possibilities for treatment of this chronic disease.

Time to ditch topical antibiotics?

Commensals promote skin regeneration and wound healing by stimulating IL-1β signaling in keratinocytes.

Proteomic and phosphoproteomic profiling of shammah induced signaling in oral keratinocytes

Shammah is a smokeless tobacco product often mixed with lime, ash, black pepper and flavorings. Exposure to shammah has been linked with dental diseases and oral squamous cell carcinoma. There is limited literature on the prevalence of shammah and its role in pathobiology of oral cancer. In this study, we developed a cellular model to understand the effect of chronic shammah exposure on oral keratinocytes. Chronic exposure to shammah resulted in increased proliferation and invasiveness of non-transformed oral keratinocytes. Quantitative proteomics of shammah treated cells compared to untreated cells led to quantification of 4712 proteins of which 402 were found to be significantly altered. In addition, phosphoproteomics analysis of shammah treated cells compared to untreated revealed hyperphosphorylation of 36 proteins and hypophosphorylation of 83 proteins (twofold, p-value ≤ 0.05). Bioinformatics analysis of significantly altered proteins showed enrichment of proteins involved in extracellular matrix interactions, necroptosis and peroxisome mediated fatty acid oxidation. Kinase-Substrate Enrichment Analysis showed significant increase in activity of kinases such as ROCK1, RAF1, PRKCE and HIPK2 in shammah treated cells. These results provide better understanding of how shammah transforms non-neoplastic cells and warrants additional studies that may assist in improved early diagnosis and treatment of shammah induced oral cancer.

175 Dynamic transcriptional and epigenetic regulation through vitamin D receptor and p63/p53 signaling in epidermal keratinocytes

175 Dynamic transcriptional and epigenetic regulation through vitamin D receptor and p63/p53 signaling in epidermal keratinocytes

NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation.

Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB-dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)-dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB-dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.

E3 ubiquitin ligase NEDD4L negatively regulates keratinocyte hyperplasia by promoting GP130 degradation.

Psoriasis is mainly characterized by abnormal hyperplasia of keratinocytes and immune cells infiltrating into the dermis and epidermis. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) is a highly conserved HECT type E3 ligase that plays an important role in regulating physiological and pathological processes. Here, we identify NEDD4L as a negative regulator of psoriasis. Nedd4l significantly inhibits imiquimod (IMQ)-induced skin hyperplasia, and this effect is attributed to the inhibitory effect of NEDD4L on IL-6/GP130 signaling in keratinocytes. Mechanistically, NEDD4L directly interacts with GP130 and mediates its Lys-27-linked ubiquitination and proteasomal degradation. Moreover, the expression of NEDD4L is downregulated in the epidermis from IMQ-treated mice and psoriasis patients and negatively correlates with the protein levels of GP130 and p-STAT3 in clinical samples. Collectively, we uncover an inhibitory role of NEDD4L in the pathogenesis of psoriasis and suggest a new therapeutic strategy for the treatment of psoriasis.

Hydrogen Peroxide, Water Channels, and Tissue Injury

Water channels, also known as aquaporins, were discovered by Peter C. Agre, the recipient of the 2003 Nobel Prize in Chemistry. In addition to facilitating transport of water, these channels have been shown to also mediate the diffusion of hydrogen peroxide across cell membranes and consequently control the biological functions of this important reactive oxygen species. Findings from multiple recent studies published in highly influential journals have further advanced our understanding on how to control the biological effects of hydrogen peroxide via targeting specific water channels. REFERENCES Hopkins RZ. Hydrogen Peroxide in biology and medicine: an overview. React Oxyg Species (Apex) 2017; 3(7):26–37. doi: https://dx.doi.org/10.20455/ros.2017.809. Bienert GP, Moller AL, Kristiansen KA, Schulz A, Moller IM, Schjoerring JK, et al. Specific aquaporins facilitate the diffusion of hydrogen peroxide across membranes. J Biol Chem 2007; 282(2):1183‒92. doi: https://dx.doi.org/10.1074/jbc.M603761200. Miller EW, Dickinson BC, Chang CJ. Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling. Proc Natl Acad Sci USA 2010; 107(36):15681‒6. doi: https://dx.doi.org/10.1073/pnas.1005776107. Watanabe S, Moniaga CS, Nielsen S, Hara-Chikuma M. Aquaporin-9 facilitates membrane transport of hydrogen peroxide in mammalian cells. Biochem Biophys Res Commun 2016; 471(1):191‒7. doi: https://dx.doi.org/10.1016/j.bbrc.2016.01.153. Hara-Chikuma M, Chikuma S, Sugiyama Y, Kabashima K, Verkman AS, Inoue S, et al. Chemokine-dependent T cell migration requires aquaporin-3-mediated hydrogen peroxide uptake. J Exp Med 2012; 209(10):1743‒52. doi: https://dx.doi.org/10.1084/jem.20112398. Hara-Chikuma M, Satooka H, Watanabe S, Honda T, Miyachi Y, Watanabe T, et al. Aquaporin-3-mediated hydrogen peroxide transport is required for NF-kappaB signalling in keratinocytes and development of psoriasis. Nat Commun 2015; 6:7454. doi: https://dx.doi.org/10.1038/ncomms8454. Satooka H, Hara-Chikuma M. Aquaporin-3 controls breast cancer cell migration by regulating hydrogen peroxide transport and its downstream cell signaling. Mol Cell Biol 2016; 36(7):1206‒18. doi: https://dx.doi.org/10.1128/MCB.00971-15. Montiel V, Bella R, Michel LYM, Esfahani H, De Mulder D, Robinson EL, et al. Inhibition of aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide. Sci Transl Med 2020; 12(564). doi: https://dx.doi.org/10.1126/scitranslmed.aay2176. Steinhorn B, Sorrentino A, Badole S, Bogdanova Y, Belousov V, Michel T. Chemogenetic generation of hydrogen peroxide in the heart induces severe cardiac dysfunction. Nat Commun 2018; 9(1):4044. doi: https://dx.doi.org/10.1038/s41467-018-06533-2. Hara-Chikuma M, Tanaka M, Verkman AS, Yasui M. Inhibition of aquaporin-3 in macrophages by a monoclonal antibody as potential therapy for liver injury. Nat Commun 2020; 11(1):5666. doi: https://dx.doi.org/10.1038/s41467-020-19491-5. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352(16):1685‒95. doi: https://dx.doi.org/10.1056/NEJMra043430. Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Rev Neurol 2010; 6(4):193‒201. doi: https://dx.doi.org/10.1038/nrneurol.2010.17.

Protein A Modulates Neutrophil and Keratinocyte Signaling and Survival in Response to Staphylococcus aureus.

The type 1 TNF-α receptor (TNFR1) has a central role in initiating both pro-inflammatory and pro-apoptotic signaling cascades in neutrophils. Considering that TNFR1 signals Staphylococcus aureus protein A (SpA), the aim of this study was to explore the interaction of this bacterial surface protein with neutrophils and keratinocytes to underscore the signaling pathways that may determine the fate of these innate immune cells in the infected tissue during staphylococcal skin infections. Using human neutrophils cultured in vitro and isogenic staphylococcal strains expressing or not protein A, we demonstrated that SpA is a potent inducer of IL-8 in neutrophils and that the induction of this chemokine is dependent on the SpA-TNFR1 interaction and p38 activation. In addition to IL-8, protein A induced the expression of TNF-α and MIP-1α highlighting the importance of SpA in the amplification of the inflammatory response. Protein A contributed to reduce neutrophil mortality prolonging their lifespan upon the encounter with S. aureus. Signaling initiated by SpA modulated the type of neutrophil cell death in vitro and during skin and soft tissue infections (SSTI) in vivo triggering the apoptotic pathway instead of necrosis. Moreover, SpA induced pro-inflammatory cytokines in keratinocytes, modulating their survival in vitro and preventing the exacerbated necrosis and ulceration of the epithelium during SSTI in vivo. Taken together, these results highlight the importance of the inflammatory signaling induced by protein A in neutrophils and skin epithelial cells. The ability of protein A to modulate the neutrophil/epithelial cell death program in the skin is of clinical relevance considering that lysis of neutrophils and epithelial cells will promote an intense inflammatory response and contribute to tissue damage, a non-desirable feature of complicated SSTI.

UBAC1/KPC2 Regulates TLR3 Signaling in Human Keratinocytes through Functional Interaction with the CARD14/CARMA2sh-TANK Complex.

CARD14/CARMA2 is a scaffold molecule whose genetic alterations are linked to human inherited inflammatory skin disorders. However, the mechanisms through which CARD14/CARMA2 controls innate immune response and chronic inflammation are not well understood. By means of a yeast two-hybrid screening, we identified the UBA Domain Containing 1 (UBAC1), the non-catalytic subunit of the E3 ubiquitin-protein ligase KPC complex, as an interactor of CARMA2sh, the CARD14/CARMA2 isoform mainly expressed in human keratinocytes. UBAC1 participates in the CARMA2sh/TANK complex and promotes K63-linked ubiquitination of TANK. In human keratinocytes, UBAC1 negatively regulates the NF-κF-activating capacity of CARMA2sh following exposure to poly (I:C), an agonist of Toll-like Receptor 3. Overall, our data indicate that UBAC1 participates in the inflammatory signal transduction pathways involving CARMA2sh.

Sargassum horneri ethanol extract ameliorates TNF-α/IFN-γ-induced inflammation in human keratinocytes and TPA-induced ear edema in mice

Sargassum horneri is a popular, and edible seaweed known for its biofunctional properties. Extracts of S. horneri were recently studied owing to the therapeutic potential in the remediation of inflammatory diseases. The present study evaluated the inhibitory effects of S. horneri 70% ethanol extracts (SHE) against tumor necrosis factor (TNF)-α/interferon (IFN)-γ-induced inflammation in HaCaT keratinocytes and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema in mice. SHE reduced the levels of epidermal and epithelial innate cytokines, interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin and inflammatory cytokines, IL-1β, IL-4, IL-6, IL-13, IFN-γ, and TNF-α in TNF-α/IFN-γ-stimulated HaCaT keratinocytes. Also, SHE decreased the expression levels of inflammatory chemokines, Eotaxin, a macrophage-derived chemokine, expressed and secreted normal T-cells, and thymus and activation regulated chemokine. Moreover, SHE suppressed the activation of nuclear factor-κB p65 signaling in HaCaT keratinocytes as well as the activation of extracellular signal-regulated kinase/p38 signaling. SHE enhanced the nuclear factor erythroid-2-related factor/heme oxygenase-mediated antioxidant defense system. SHE also reduced the ear thickness, infiltration of inflammatory cells, hyperplasia, and hyperkeratosis in the TPA-induced ear edema mouse model. The anti-inflammatory effects of SHE were implicated in the anti-inflammatory effects of SHE in TNF-α/IFN-γ-induced inflammation in HaCaT keratinocytes and TPA-induced ear edema in mice. This study suggested that SHE has anti-inflammatory effects on TNF-α/IFN-γ-induced inflammation in keratinocytes and TPA-induced ear edema in a mice model. Further research could develop SHE as a food supplement/nutricosmetic to enhance protective effects against inflammatory skin diseases.