{"title":"Foxp3+ Treg control allergic skin inflammation by restricting IFN-γ-driven neutrophilic infiltration and NETosis","authors":"","doi":"10.1016/j.jdermsci.2024.05.002","DOIUrl":"10.1016/j.jdermsci.2024.05.002","url":null,"abstract":"<div><h3>Background</h3><p>Atopic dermatitis (AD), a chronic inflammatory skin disease with T cell activation as a key feature, in which Th2 cell–mediated responses play a pivotal role. Regulatory T cells (Treg) are central immune cells that restrict autoimmunity and inflammation in the body. Patients with immune dysregulation, polyendocrinopathy, or enteropathy X-linked syndrome, an immune disease characterized by a deficiency in Treg, develop skin inflammation and allergic disorders, indicating that Treg play a crucial role in the development of allergic skin inflammation.</p></div><div><h3>Objective</h3><p>we investigated the underlying mechanisms by which Treg control cutaneous allergic inflammation.</p></div><div><h3>Methods</h3><p>An allergic skin inflammation mouse model was constructed using MC903, and Treg-depleted mouse model was constructed using diphtheria toxin. Neutralization of IFN-γ was constructed using anti-mouse-IFN-γ mouse antibody. Neutrophil infiltration was analyzed by flow cytometry and immunohistochemistry. Neutrophil extracellular traps (NETs), a process called NETosis, were detected using immunofluorescence. In vitro neutrophil stimulation and immunocytochemistry was conducted to demonstrate the effect of IFN-γ on NETosis.</p></div><div><h3>Results</h3><p>The depletion of Foxp3<sup>+</sup> Treg led to significantly exacerbated AD-like skin inflammation, including increased recruitment of neutrophils and expression of Th1 cytokine IFN-γ. Neutrophil infiltrating in skin of Treg-depleted mice released more NETs than wild type. Neutralization of IFN-γ abolished neutrophil infiltration and NETosis in Treg-depleted mice. Neutrophils stimulated with IFN-γ were more prone to release NETs <em>in vitro</em>. Finally, Foxp3<sup>+</sup> Treg control cutaneous allergic inflammation by regulating IFN-γ-driven neutrophilic infiltration and NETosis.</p></div><div><h3>Conclusion</h3><p>Our results highlight the previously underestimated Treg-IFN-γ-neutrophil inflammatory axis.</p></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"115 1","pages":"Pages 2-12"},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141051237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RAS-activated PI3K/AKT signaling sustains cellular senescence via P53/P21 axis in experimental models of psoriasis","authors":"","doi":"10.1016/j.jdermsci.2024.03.002","DOIUrl":"10.1016/j.jdermsci.2024.03.002","url":null,"abstract":"<div><h3>Background</h3><p>Psoriasis is a chronic immune-mediated skin disease in which upper epidermal keratinocytes exhibit a senescent-like phenotype. In psoriatic skin, a variety of inflammatory cytokines can activate intracellular pathways including phosphatidylinositol 3-kinase (PI3K)/AKT signaling and RAS effectors. AKT and RAS participate to cellular senescence, but currently their role in senescence responses occurring in psoriasis have not yet been investigated.</p></div><div><h3>Objective</h3><p>The role of AKT molecular axis and RAS activation was evaluated in the context of cellular senescence in psoriasis disease.</p></div><div><h3>Methods</h3><p>RAS/AKT involvement in senescence was analyzed in psoriatic keratinocytes cultures subjected to multiple passages to promote senescence <em>in vitro</em>, as well as in skin lesions of patients affected by psoriasis. The impact of pharmacological inhibition of PI3K/AKT pathway on senescence and inflammation responses was tested in senescent psoriatic keratinocytes and in a psoriasiform dermatitis murine model induced by RAS overexpression in the upper epidermis of mice.</p></div><div><h3>Results</h3><p>We found AKT hyperactivation associated to the upregulation of senescence markers, in senescent psoriatic keratinocyte cultures, as well as in skin lesions of psoriatic patients. AKT-induced senescence was sustained by constitutive RAS activation, and down-stream responses were mediated by P53/P21 axis. PI3K/AKT inhibition contrasted senescence processes induced by cytokines in psoriatic keratinocytes. Additionally, RAS-induced psoriasis-like dermatitis in mice was accompanied by AKT upregulation, increase of senescence marker expression and by skin inflammation. In this model, both senescence and inflammation were significantly reduced by selective AKT inhibition.</p></div><div><h3>Conclusion</h3><p>Therefore, targeting RAS-AKT pathway could be a promising novel strategy to counteract multiple psoriasis symptoms.</p></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"115 1","pages":"Pages 21-32"},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0923181124000343/pdfft?md5=83c778d0d309fc983999cd4edf7b3056&pid=1-s2.0-S0923181124000343-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140271184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shan Zhang , Xiaokai Fang , Beilei Xu, Yuan Zhou, Fang Li, Yuwen Gao, Yang Luo, Xu Yao, Xiaochun Liu
{"title":"Comprehensive analysis of phenotypes and transcriptome characteristics reveal the best atopic dermatitis mouse model induced by MC903","authors":"Shan Zhang , Xiaokai Fang , Beilei Xu, Yuan Zhou, Fang Li, Yuwen Gao, Yang Luo, Xu Yao, Xiaochun Liu","doi":"10.1016/j.jdermsci.2024.05.003","DOIUrl":"10.1016/j.jdermsci.2024.05.003","url":null,"abstract":"<div><h3>Background</h3><p>Although several mouse models of exogenous-agent<strong>–</strong>induced atopic dermatitis (AD) are currently available, the lack of certainty regarding their similarity with human AD has limited their scientific value. Thus, comprehensive evaluation of the characteristics of mouse models and their similarity with human AD is essential.</p></div><div><h3>Objective</h3><p>To compare six different exogenous-agent<strong>–</strong>induced AD mouse models and find out the optimum models for study.</p></div><div><h3>Methods</h3><p>Female BALB/c mice underwent induction of AD-like dermatitis by MC903 alone or in combination with ovalbumin (OVA), dinitrofluorobenzene (DNFB) alone or in combination with OVA, OVA alone, or <em>Staphylococcus aureus</em>. Gross phenotype, total immunoglobulin E (IgE) level, histopathological manifestations, and skin lesion transcriptome were analyzed, and metagenomic sequencing of the gut microbiome was performed.</p></div><div><h3>Results</h3><p>The DNFB plus OVA model showed the highest disease severity, while the OVA model showed the lowest severity. The MC903 and MC903 plus OVA models showed high expression of T-helper (Th)2- and Th17-related genes; the DNFB and DNFB plus OVA models showed upregulation of Th1-, Th2-, and Th17-related genes; while the <em>S. aureus</em> inoculation model showed more enhanced Th1 and Th17 immune responses. In contrast to the other models, the OVA-induced model showed the lowest expression levels of inflammation-related genes, while the MC903 model shared the largest overlap with human AD profiles. The intestinal microbiota of all groups showed significant differences after modeling.</p></div><div><h3>Conclusion</h3><p>Each AD mouse model exhibited different characteristics. The MC903 model was the best to recapitulate most features of human AD among these exogenous-agent<strong>–</strong>induced AD models.</p></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"114 3","pages":"Pages 104-114"},"PeriodicalIF":4.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141145412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jung-Min Shin, Yeounkuk Sung, Dongkyun Hong, Kyung-Eun Jung, Young-Joon Seo, Chang-Deok Kim, Young Lee
{"title":"Differences in activation of β-catenin in outer root sheath cells between the type of JAK inhibitor: An alternative mechanism promoting hair growth by JAK inhibitors in alopecia areata","authors":"Jung-Min Shin, Yeounkuk Sung, Dongkyun Hong, Kyung-Eun Jung, Young-Joon Seo, Chang-Deok Kim, Young Lee","doi":"10.1016/j.jdermsci.2024.04.005","DOIUrl":"10.1016/j.jdermsci.2024.04.005","url":null,"abstract":"","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"114 3","pages":"Pages 148-150"},"PeriodicalIF":4.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140909564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Metabolome analyses of skin dialysate: Insights into skin interstitial fluid biomarkers","authors":"Akihiko Oharazawa , Gulinu Maimaituxun , Koichi Watanabe , Takeshi Nishiyasu , Naoto Fujii","doi":"10.1016/j.jdermsci.2024.04.001","DOIUrl":"10.1016/j.jdermsci.2024.04.001","url":null,"abstract":"<div><h3>Background</h3><p>Metabolites in biofluids can serve as biomarkers for diagnosing diseases and monitoring body conditions. Among the available biofluids, interstitial fluid (ISF) in the skin has garnered considerable attention owing to its advantages, which include inability to clot, easy access to the skin, and possibility of incorporating wearable devices. However, the scientific understanding of skin ISF composition is limited.</p></div><div><h3>Objective</h3><p>In this study, we aimed to compare metabolites between skin dialysate containing metabolites from the skin ISF and venous blood (plasma) samples, both collected under resting states.</p></div><div><h3>Methods</h3><p>We collected forearm skin dialysate using intradermal microdialysis alongside venous blood (plasma) samples from 12 healthy young adults. We analyzed these samples using capillary electrophoresis–fourier transform mass spectrometry–based metabolomics (CE–FTMS).</p></div><div><h3>Results</h3><p>Significant positive correlations were observed in 39 metabolites between the skin dialysate and plasma, including creatine (a mitochondrial disease biomarker), 1-methyladenosine (an early detection of cancer biomarker), and trimethylamine N-oxide (a posterior predictor of heart failure biomarker). Based on the Human Metabolome Technologies database, we identified 12 metabolites unique to forearm skin dialysate including nucleic acids, benzoate acids, fatty acids, amino acids, ascorbic acid, 3-methoxy-4-hydroxyphenylethyleneglycol (an Alzheimer’s disease biomarker), and cysteic acid (an acute myocardial infarction biomarker).</p></div><div><h3>Conclusion</h3><p>We show that some venous blood biomarkers may be predicted from skin dialysate or skin ISF, and that these fluids may serve as diagnostic and monitoring tools for health and clinical conditions.</p></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"114 3","pages":"Pages 141-147"},"PeriodicalIF":4.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0923181124000665/pdfft?md5=8ecc49ad5ecd889243a6e719b14312fe&pid=1-s2.0-S0923181124000665-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140917580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yang Luo , Xiaokai Fang , Yuan Zhou , Yu Zhang , Wei Li , Sean X. Leng , Xu Yao , Xiaochun Liu
{"title":"Senescent fibroblasts and innate immune cell activation might play a role in the pathogenesis of elderly atopic dermatitis","authors":"Yang Luo , Xiaokai Fang , Yuan Zhou , Yu Zhang , Wei Li , Sean X. Leng , Xu Yao , Xiaochun Liu","doi":"10.1016/j.jdermsci.2024.04.002","DOIUrl":"10.1016/j.jdermsci.2024.04.002","url":null,"abstract":"<div><h3>Background</h3><p>Elderly atopic dermatitis (AD) is a subtype of AD defined by age (≥ 60 years). The molecular characteristics of elderly AD remain to be clarified.</p></div><div><h3>Objective</h3><p>We sought to characterize the molecular features of skin lesions and peripheral blood mononuclear cells (PBMCs) in patients with AD across different age, focusing on elderly AD.</p></div><div><h3>Methods</h3><p>Skin and PBMCs samples were used for RNA sequencing. Analysis of differentially expressed genes and gene set variation analysis were performed. Immunofluorescence staining, quantitative real-time PCR (qRT-PCR), flow cytometry and transwell assay were used for validation.</p></div><div><h3>Results</h3><p>Compared with healthy controls, the skin transcriptome of AD patients showed common signatures of AD, like barrier dysfunction and enhanced Th1/Th2/Th17 immune pathways. In PBMCs, the expression of Th1/Th2 response genes was more remarkable in adult AD, while expression of Th17-related genes was significantly higher in childhood AD. The gene modules associated with natural killer (NK) cells were downregulated in elderly AD. In skin lesions, elderly AD exhibited enrichment of macrophages, fibroblasts and senescence-associated secretory phenotype (SASP) related genes. The correlation among fibroblasts, SASP and innate immune cells were revealed by the co-localization of fibroblasts, macrophages and NK cells in the lesions across different age groups. Fibroblasts under inflammation or senescence could induce stronger chemotaxis of macrophages and NK cells.</p></div><div><h3>Conclusion</h3><p>We identified the molecular phenotypes of skin lesions and PBMCs in elderly AD individuals. Fibroblasts, innate immune cells, and SASP might play important roles in the pathogenesis of elderly AD.</p></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"114 3","pages":"Pages 94-103"},"PeriodicalIF":4.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140795036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}