Pub Date : 2025-03-01DOI: 10.1016/j.jdermsci.2025.01.004
Ken Okamura, Tamio Suzuki
Vitiligo, a complex autoimmune disorder characterized by melanocyte destruction, arises from an intricate interplay of genetic, epigenetic, immune, and environmental factors. Genome-wide association studies (GWAS) have identified over 50 susceptibility loci, including key genes within the MHC region and those involved in immunity, oxidative stress, and melanogenesis. Concurrently, epigenetic research has unraveled regulatory networks critical to vitiligo pathogenesis, with a focus on DNA methylation and non-coding RNAs (e.g., microRNAs, long non-coding RNAs, and circular RNAs). These advancements provide deeper insights into gene regulation, immune processes, and cellular dynamics. This review integrates findings from genetic and epigenetic studies to offer a comprehensive understanding of molecular mechanisms of vitiligo, paving the way for innovative, personalized therapeutic approaches.
{"title":"Genetics and epigenetics in vitiligo","authors":"Ken Okamura, Tamio Suzuki","doi":"10.1016/j.jdermsci.2025.01.004","DOIUrl":"10.1016/j.jdermsci.2025.01.004","url":null,"abstract":"<div><div>Vitiligo, a complex autoimmune disorder characterized by melanocyte destruction, arises from an intricate interplay of genetic, epigenetic, immune, and environmental factors. Genome-wide association studies (GWAS) have identified over 50 susceptibility loci, including key genes within the MHC region and those involved in immunity, oxidative stress, and melanogenesis. Concurrently, epigenetic research has unraveled regulatory networks critical to vitiligo pathogenesis, with a focus on DNA methylation and non-coding RNAs (e.g., microRNAs, long non-coding RNAs, and circular RNAs). These advancements provide deeper insights into gene regulation, immune processes, and cellular dynamics. This review integrates findings from genetic and epigenetic studies to offer a comprehensive understanding of molecular mechanisms of vitiligo, paving the way for innovative, personalized therapeutic approaches.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"117 3","pages":"Pages 45-51"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076758","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}
Pub Date : 2025-03-01DOI: 10.1016/j.jdermsci.2024.12.002
Xinya Xu , Xinhua Lu , Yue Zheng , Yang Xie , Wei Lai
Background
The cGAS-STING axis, a DNA sensor pathway, has recently emerged as a key hub in sensing stress signals and initiating the immune cascade in several diseases. However, its role in the pathogenesis of vitiligo remains unclear.
Objective
To explore the pathogenic role of the cGAS-STING axis in linking oxidative stress and CD8+ T-cell-mediated anti-melanocytic immunity in vitiligo.
Methods
The expression status of the cGAS-STING axis and cytosolic mtDNA were evaluated in the oxidatively stressed epidermal cells and vitiligo perilesional skin, respectively. Then, we investigated the activation of cGAS-STING axis in mtDNA-treated melanocytes, and the influence of cGAS or STING silencing on mtDNA-induced melanocytes pyroptosis. Finally, the paracrine effects of melanocytes pyroptosis on CD8+ T cell activation were explored.
Results
We initially demonstrated that the cGAS-STING axis in melanocytes was highly susceptible to oxidative stress and activated in the vitiliginous melanocytes of perilesional skin, accompanied by enhanced cytosolic mtDNA accumulation. Our mechanistic in vitro experiments confirmed that oxidative stress-induced mitochondrial damage in epidermal cells led to cytosolic mtDNA accumulation, which served as a trigger in activating the cGAS-STING axis in melanocytes. Furthermore, the cytosolic mtDNA-cGAS-STING axis was verified to mediate melanocytes pyroptosis. More importantly, we found that IL-1β and IL-18 produced by pyroptotic melanocytes promoted the activation of CD8+ T cells from patients with vitiligo.
Conclusion
The present study confirmed that the cytosolic mtDNA-cGAS-STING axis of melanocytes played an important role in oxidative stress-triggered CD8+ T-cell response, providing novel insights into mechanisms underlying vitiligo onset.
{"title":"Cytosolic mtDNA-cGAS-STING axis mediates melanocytes pyroptosis to promote CD8+ T-cell activation in vitiligo","authors":"Xinya Xu , Xinhua Lu , Yue Zheng , Yang Xie , Wei Lai","doi":"10.1016/j.jdermsci.2024.12.002","DOIUrl":"10.1016/j.jdermsci.2024.12.002","url":null,"abstract":"<div><h3>Background</h3><div>The cGAS-STING axis, a DNA sensor pathway, has recently emerged as a key hub in sensing stress signals and initiating the immune cascade in several diseases. However, its role in the pathogenesis of vitiligo remains unclear.</div></div><div><h3>Objective</h3><div>To explore the pathogenic role of the cGAS-STING axis in linking oxidative stress and CD8<sup>+</sup> T-cell-mediated anti-melanocytic immunity in vitiligo.</div></div><div><h3>Methods</h3><div>The expression status of the cGAS-STING axis and cytosolic mtDNA were evaluated in the oxidatively stressed epidermal cells and vitiligo perilesional skin, respectively. Then, we investigated the activation of cGAS-STING axis in mtDNA-treated melanocytes, and the influence of cGAS or STING silencing on mtDNA-induced melanocytes pyroptosis. Finally, the paracrine effects of melanocytes pyroptosis on CD8<sup>+</sup> T cell activation were explored.</div></div><div><h3>Results</h3><div>We initially demonstrated that the cGAS-STING axis in melanocytes was highly susceptible to oxidative stress and activated in the vitiliginous melanocytes of perilesional skin, accompanied by enhanced cytosolic mtDNA accumulation. Our mechanistic <em>in vitro</em> experiments confirmed that oxidative stress-induced mitochondrial damage in epidermal cells led to cytosolic mtDNA accumulation, which served as a trigger in activating the cGAS-STING axis in melanocytes. Furthermore, the cytosolic mtDNA-cGAS-STING axis was verified to mediate melanocytes pyroptosis. More importantly, we found that IL-1β and IL-18 produced by pyroptotic melanocytes promoted the activation of CD8<sup>+</sup> T cells from patients with vitiligo.</div></div><div><h3>Conclusion</h3><div>The present study confirmed that the cytosolic mtDNA-cGAS-STING axis of melanocytes played an important role in oxidative stress-triggered CD8<sup>+</sup> T-cell response, providing novel insights into mechanisms underlying vitiligo onset.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"117 3","pages":"Pages 61-70"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191565","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}
Mechanical alloknesis (m-alloknesis) is itch hypersensitivity induced by normally innocuous stimuli. It is sometimes observed in dry skin based itch-related diseases such as atopic dermatitis (AD), and often triggers the vicious itch-scratch cycle. The acetone-ether and water (AEW) mouse model mimics dry skin-induced m-alloknesis, yet its underlying mechanism remains unclear. Janus kinase (JAK) inhibitors are used to treat AD, but their effects on m-alloknesis are not fully known.
Objective
To reveal the effects of various oral JAK inhibitors on m-alloknesis and their action points, using AEW model.
Methods
AEW model was prepared by treatment with a mixture of acetone-ether, and they were orally administrated a JAK1/2 inhibitor baricitinib, a selective JAK1 inhibitor abrocitinib, or a JAK2 selective inhibitor AZ960, and evaluated m-alloknesis score as the total number of scratching responses in 30 mechanical stimulations. To further elucidate the mechanism of action, IL-4, IL-13 or thymic stromal lymphopoietin (TSLP) or their neutralizing antibodies were also applied to mice. In addition, the levels of these cytokines in mouse skin were measured using multiple immunoassays.
Results
All of JAK inhibitors effectively reduced m-alloknesis, with abrocitinib demonstrating the most significant inhibition. The neutralizing antibodies against IL-4, IL-13, and TSLP inhibited m-alloknesis in AEW mice. Intradermal administration of IL-4, IL-13, or TSLP induced m-alloknesis, and abrocitinib effectively mitigated each cytokine-induced response. Highly sensitive assays detected IL-4, IL-13, IL-31 and TSLP in AEW-treated skin, with TSLP levels significantly increased.
Conclusion
Type 2 cytokine-JAK1 signaling is involved in the development of m-alloknesis in dry skin.
{"title":"Type 2 cytokine-JAK1 signaling is involved in the development of dry skin-induced mechanical alloknesis","authors":"Yui Toyosawa , Eriko Komiya , Takahide Kaneko , Yasushi Suga , Mitsutoshi Tominaga , Kenji Takamori","doi":"10.1016/j.jdermsci.2024.10.002","DOIUrl":"10.1016/j.jdermsci.2024.10.002","url":null,"abstract":"<div><h3>Background</h3><div>Mechanical alloknesis (m-alloknesis) is itch hypersensitivity induced by normally innocuous stimuli. It is sometimes observed in dry skin based itch-related diseases such as atopic dermatitis (AD), and often triggers the vicious itch-scratch cycle. The acetone-ether and water (AEW) mouse model mimics dry skin-induced m-alloknesis, yet its underlying mechanism remains unclear. Janus kinase (JAK) inhibitors are used to treat AD, but their effects on m-alloknesis are not fully known.</div></div><div><h3>Objective</h3><div>To reveal the effects of various oral JAK inhibitors on m-alloknesis and their action points, using AEW model.</div></div><div><h3>Methods</h3><div>AEW model was prepared by treatment with a mixture of acetone-ether, and they were orally administrated a JAK1/2 inhibitor baricitinib, a selective JAK1 inhibitor abrocitinib, or a JAK2 selective inhibitor AZ960, and evaluated m-alloknesis score as the total number of scratching responses in 30 mechanical stimulations. To further elucidate the mechanism of action, IL-4, IL-13 or thymic stromal lymphopoietin (TSLP) or their neutralizing antibodies were also applied to mice. In addition, the levels of these cytokines in mouse skin were measured using multiple immunoassays.</div></div><div><h3>Results</h3><div>All of JAK inhibitors effectively reduced m-alloknesis, with abrocitinib demonstrating the most significant inhibition. The neutralizing antibodies against IL-4, IL-13, and TSLP inhibited m-alloknesis in AEW mice. Intradermal administration of IL-4, IL-13, or TSLP induced m-alloknesis, and abrocitinib effectively mitigated each cytokine-induced response. Highly sensitive assays detected IL-4, IL-13, IL-31 and TSLP in AEW-treated skin, with TSLP levels significantly increased.</div></div><div><h3>Conclusion</h3><div>Type 2 cytokine-JAK1 signaling is involved in the development of m-alloknesis in dry skin.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"117 3","pages":"Pages 52-60"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142775917","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}
Xeroderma pigmentosum (XP) is caused by impaired DNA repair of UV-induced dipyrimidine-photoproducts. XP cells also show impaired repair/removal of ROS or oxidative DNA lesions caused by UV or 4-nitroquinolline 1-oxide (4NQO). Gene profiling indicated that inflammatory response-related genes are significantly upregulated after UV exposure in XP-A model mice.
Objective
Since XP cells are in the state of oxidative stress and inflammation, we aimed to search for therapeutic agents from anti-oxidants/anti-inflammatory drugs, that potentially improve XP symptoms.
Methods
Several antioxidants were examined for reducing 4NQO-induced oxidative cytotoxicity or UV-induced oxidative DNA damage in XP-A cells. Among them, we focused on melatonin and evaluated its improving effect for Xpa-deficient MEF on UV-induced cytotoxicity and ROS production, and for Xpa-deficient mice on UV-induced skin tumorigenesis and auditory brainstem responses as one of the neurological symptoms.
Results
Melatonin and nicotinamide attenuated 4NQO-induced oxidative cytotoxicity. UV-induced intracellular ROS production and cytotoxicity were improved by melatonin for Xpa-deficient MEF. Finally, the administration of melatonin mitigated UV-induced skin inflammation and tumorigenesis and suppressed hearing deterioration in Xpa-deficient mice.
Conclusion
Our results show that melatonin could alleviate XP symptoms through its anti-inflammatory and antioxidant properties.
{"title":"Melatonin mitigates UV-induced tumorigenesis and suppresses hearing function deterioration in Xpa-deficient mice","authors":"Mariko Tsujimoto , Takeshi Fujita , Tatsuya Furukawa , Yaeno Arima , Ken-Ichi Nibu , Chikako Nishigori","doi":"10.1016/j.jdermsci.2025.01.003","DOIUrl":"10.1016/j.jdermsci.2025.01.003","url":null,"abstract":"<div><h3>Background</h3><div>Xeroderma pigmentosum (XP) is caused by impaired DNA repair of UV-induced dipyrimidine-photoproducts. XP cells also show impaired repair/removal of ROS or oxidative DNA lesions caused by UV or 4-nitroquinolline 1-oxide (4NQO). Gene profiling indicated that inflammatory response-related genes are significantly upregulated after UV exposure in XP-A model mice.</div></div><div><h3>Objective</h3><div>Since XP cells are in the state of oxidative stress and inflammation, we aimed to search for therapeutic agents from anti-oxidants/anti-inflammatory drugs, that potentially improve XP symptoms.</div></div><div><h3>Methods</h3><div>Several antioxidants were examined for reducing 4NQO-induced oxidative cytotoxicity or UV-induced oxidative DNA damage in XP-A cells. Among them, we focused on melatonin and evaluated its improving effect for <em>Xpa</em>-deficient MEF on UV-induced cytotoxicity and ROS production, and for <em>Xpa-</em>deficient mice on UV-induced skin tumorigenesis and auditory brainstem responses as one of the neurological symptoms.</div></div><div><h3>Results</h3><div>Melatonin and nicotinamide attenuated 4NQO-induced oxidative cytotoxicity. UV-induced intracellular ROS production and cytotoxicity were improved by melatonin for <em>Xpa</em>-deficient MEF. Finally, the administration of melatonin mitigated UV-induced skin inflammation and tumorigenesis and suppressed hearing deterioration in <em>Xpa</em>-deficient mice.</div></div><div><h3>Conclusion</h3><div>Our results show that melatonin could alleviate XP symptoms through its anti-inflammatory and antioxidant properties.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"117 3","pages":"Pages 81-87"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076759","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}
Pub Date : 2025-03-01DOI: 10.1016/j.jdermsci.2025.02.001
Qingyan Luo , Xiaoheng Wang , Yanling Zhang , Wenrong Xie , Lina Liang , Yingping Xu , Yunshen Liang , Suyun Ji
Background
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular endothelial dysfunction and damage, immune dysregulation and fibrosis. Endothelial mesenchymal transition (EndoMT) has been implicated in the skin fibrosis of SSc. Many studies have demonstrated that janus kinase type2 (JAK2) inhibitor can alleviate skin fibrosis in both SSc patients and bleomycin (BLM)-induced mouse models of SSc. However, the potential therapeutic effect of JAK2 inhibitor on EndoMT in SSc skin, along with the underlying molecular mechanisms, remains unexplored.
Objective
To investigate the effects of JAK2 inhibitor on the EndoMT in SSc skin and to elucidate the associated molecular mechanisms.
Methods
Wild-type female C57BL/6 mice were divided into several groups to assess the effects of JAK2 inhibitor on EndoMT through H&E staining, masson staining, immunofluorescence and single-cell RNA-sequencing (scRNA-seq). Cultured human umbilical vein endothelial cells (HUVECs) were used to explore the mechanism of action of JAK2 inhibitor on EndoMT using immunofluorescence, quantitative RT-PCR, RNA sequencing and western blot.
Results
JAK2 inhibition improved skin fibrosis, reduced CD31/α-SMA co-localisation and the number of EndoMT-activated vascular endothelial cells in bleomycin-induced SSc mice. Treatment of HUVECs with TGF-β or BLM led to a myofibroblast-like morphology and markers, along with downregulation of endothelial cell features, which were reversed following JAK2 inhibition. The activation of the PI3K/Akt/mTOR pathway was involved in EndoMT in HUVECs induced by TGF-β/BLM, and this activation was attenuated by JAK2 inhibition.
Conclusions
JAK2 inhibitor may serve as an effective treatment for EndoMT in SSc, potentially through modulation of the PI3K/Akt/mTOR signaling pathway.
{"title":"The role and mechanism of JAK2 inhibitor in endothelial mesenchymal transition in systemic sclerosis","authors":"Qingyan Luo , Xiaoheng Wang , Yanling Zhang , Wenrong Xie , Lina Liang , Yingping Xu , Yunshen Liang , Suyun Ji","doi":"10.1016/j.jdermsci.2025.02.001","DOIUrl":"10.1016/j.jdermsci.2025.02.001","url":null,"abstract":"<div><h3>Background</h3><div>Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular endothelial dysfunction and damage, immune dysregulation and fibrosis. Endothelial mesenchymal transition (EndoMT) has been implicated in the skin fibrosis of SSc. Many studies have demonstrated that janus kinase type2 (JAK2) inhibitor can alleviate skin fibrosis in both SSc patients and bleomycin (BLM)-induced mouse models of SSc. However, the potential therapeutic effect of JAK2 inhibitor on EndoMT in SSc skin, along with the underlying molecular mechanisms, remains unexplored.</div></div><div><h3>Objective</h3><div>To investigate the effects of JAK2 inhibitor on the EndoMT in SSc skin and to elucidate the associated molecular mechanisms.</div></div><div><h3>Methods</h3><div>Wild-type female C57BL/6 mice were divided into several groups to assess the effects of JAK2 inhibitor on EndoMT through H&E staining, masson staining, immunofluorescence and single-cell RNA-sequencing (scRNA-seq). Cultured human umbilical vein endothelial cells (HUVECs) were used to explore the mechanism of action of JAK2 inhibitor on EndoMT using immunofluorescence, quantitative RT-PCR, RNA sequencing and western blot.</div></div><div><h3>Results</h3><div>JAK2 inhibition improved skin fibrosis, reduced CD31/α-SMA co-localisation and the number of EndoMT-activated vascular endothelial cells in bleomycin-induced SSc mice. Treatment of HUVECs with TGF-β or BLM led to a myofibroblast-like morphology and markers, along with downregulation of endothelial cell features, which were reversed following JAK2 inhibition. The activation of the PI3K/Akt/mTOR pathway was involved in EndoMT in HUVECs induced by TGF-β/BLM, and this activation was attenuated by JAK2 inhibition.</div></div><div><h3>Conclusions</h3><div>JAK2 inhibitor may serve as an effective treatment for EndoMT in SSc, potentially through modulation of the PI3K/Akt/mTOR signaling pathway.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"117 3","pages":"Pages 71-80"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538268","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}
Altered Fli1 expression is associated with various autoimmune diseases, yet its impact on B cells remains unexplored.
Objective
This study investigated the direct effects of Fli1 depletion on B cell populations, focusing on age-associated B cells (ABCs).
Methods
Splenocytes of Fli1 BcKO (Cd19-Cre+/-; Fli1flox/flox) and Cd19-Cre+/- mice were analyzed flow cytometrically. Transcriptional/epigenetic profiles of Cd11b+Cd11c+ ABCs were examined by RNA-sequencing and ATAC-sequencing.
Results
Fli1 BcKO mice displayed a notable reduction in follicular and marginal zone B cells, with a concurrent rise in newly formed B cells compared to Cd19-Cre+/- mice. Additionally, a striking increase in B-1 B cells, as well as Cd11b+Cd11c+ or T-bet+Cd11c+ ABCs, was observed in Fli1 BcKO mice. Furthermore, these mice exhibited elevated Cd138 levels in follicular B cells. Conducting transcriptional analyses of Fli1-depleted ABCs unveiled upregulated genes associated with cell-cell adhesion, coupled with downregulated genes linked to cell activation or immune responses. Exploring the chromatin landscape found that Fli1 depletion dysregulated the chromatin accessibility of the interferon regulatory factor family, implying potential roles in autoimmunity.
Conclusion
These findings suggest complex modulations of B cell populations and immune-related gene expression due to Fli1 deficiency, shedding light on its involvement in autoimmune processes.
{"title":"Impact of Fli1 deletion on B cell populations: A focus on age-associated B cells and transcriptional dynamics","authors":"Kentaro Awaji , Sayaka Shibata , Asumi Koyama , Toyoki Yamamoto , Yuki Fukui , Satoshi Toyama , Jun Omatsu , Yuta Norimatsu , Tetsuya Ikawa , Yusuke Watanabe , Takuya Miyagawa , Takashi Yamashita , Yukiteru Nakayama , Maria Trojanowska , Shinichi Sato , Yoshihide Asano","doi":"10.1016/j.jdermsci.2024.12.003","DOIUrl":"10.1016/j.jdermsci.2024.12.003","url":null,"abstract":"<div><h3>Background</h3><div>Altered Fli1 expression is associated with various autoimmune diseases, yet its impact on B cells remains unexplored.</div></div><div><h3>Objective</h3><div>This study investigated the direct effects of Fli1 depletion on B cell populations, focusing on age-associated B cells (ABCs).</div></div><div><h3>Methods</h3><div>Splenocytes of <em>Fli1</em> BcKO (<em>Cd19-Cre</em><sup>+/-</sup>; <em>Fli1</em><sup><em>flox/flox</em></sup>) and <em>Cd19-Cre</em><sup>+/-</sup> mice were analyzed flow cytometrically. Transcriptional/epigenetic profiles of Cd11b<sup>+</sup>Cd11c<sup>+</sup> ABCs were examined by RNA-sequencing and ATAC-sequencing.</div></div><div><h3>Results</h3><div><em>Fli1</em> BcKO mice displayed a notable reduction in follicular and marginal zone B cells, with a concurrent rise in newly formed B cells compared to <em>Cd19-Cre</em><sup><em>+/-</em></sup> mice. Additionally, a striking increase in B-1 B cells, as well as Cd11b<sup>+</sup>Cd11c<sup>+</sup> or T-bet<sup>+</sup>Cd11c<sup>+</sup> ABCs, was observed in <em>Fli1</em> BcKO mice. Furthermore, these mice exhibited elevated Cd138 levels in follicular B cells. Conducting transcriptional analyses of Fli1-depleted ABCs unveiled upregulated genes associated with cell-cell adhesion, coupled with downregulated genes linked to cell activation or immune responses. Exploring the chromatin landscape found that Fli1 depletion dysregulated the chromatin accessibility of the interferon regulatory factor family, implying potential roles in autoimmunity.</div></div><div><h3>Conclusion</h3><div>These findings suggest complex modulations of B cell populations and immune-related gene expression due to Fli1 deficiency, shedding light on its involvement in autoimmune processes.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"117 2","pages":"Pages 19-29"},"PeriodicalIF":4.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143019012","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}
Pub Date : 2025-02-01DOI: 10.1016/j.jdermsci.2025.01.002
Thomas Steadman, Steven O’Reilly
Background
Systemic Sclerosis (SSc) is an idiopathic rheumatic inflammatory disease that is characterised by inflammation and skin fibrosis. Type I interferon is significantly elevated in the disease.
Objective
The objective of this study is to determine the role of the TCA cycle metabolite fumarate in SSc.
Methods
CD14 + cells were isolated from 12 SSc patients and healthy controls. Fumarate hydratase and Interferon dependant genes were quantified by qPCR. In vitro inhibition of STING using a small molecule STING inhibitor and enforced mitophagy was induced in vitro and IFN-β release was quantified. VDAC1 inhibitor was used to determine the role of mt DNA release in IFN-β induction. In whole skin biopsies fumarate and succinate was quantified.
Results
Fumarate Hydratase is significantly reduced in SSc monocytes. Type I interferon is also elevated in monocytes from SSc donors compared to controls. The mitochondrial-specific stress marker GDF-15 was significantly elevated in SSc monocytes. Blockade of the cGAS-STING pathway chemically reduced interferon-β release and induced mitophagy also retarded release of the cytokine in response to LPS stimulation. Inhibition of VDAC1 mitigated IFN-β, as did the depletion of mitochondria in cells. Furthermore, the itaconate derivative 4-octyl itaconate reduced IFN-β induction in SSc monocytes, that was downstream of mitochondrial nucleic acid release. Fumarate, but not succinate was elevated in whole skin biopsies.
Conclusion
Fumarate metabolism links interferon release in SSc and may underlie the aberrant expression of interferon in SSc via cytosolic DNA released from mitochondria.
{"title":"Aberrant fumarate metabolism links interferon release in diffuse systemic sclerosis","authors":"Thomas Steadman, Steven O’Reilly","doi":"10.1016/j.jdermsci.2025.01.002","DOIUrl":"10.1016/j.jdermsci.2025.01.002","url":null,"abstract":"<div><h3>Background</h3><div>Systemic Sclerosis (SSc) is an idiopathic rheumatic inflammatory disease that is characterised by inflammation and skin fibrosis. Type I interferon is significantly elevated in the disease.</div></div><div><h3>Objective</h3><div>The objective of this study is to determine the role of the TCA cycle metabolite fumarate in SSc.</div></div><div><h3>Methods</h3><div>CD14 + cells were isolated from 12 SSc patients and healthy controls. Fumarate hydratase and Interferon dependant genes were quantified by qPCR. In vitro inhibition of STING using a small molecule STING inhibitor and enforced mitophagy was induced in vitro and IFN-β release was quantified. VDAC1 inhibitor was used to determine the role of mt DNA release in IFN-β induction. In whole skin biopsies fumarate and succinate was quantified.</div></div><div><h3>Results</h3><div>Fumarate Hydratase is significantly reduced in SSc monocytes. Type I interferon is also elevated in monocytes from SSc donors compared to controls. The mitochondrial-specific stress marker GDF-15 was significantly elevated in SSc monocytes. Blockade of the cGAS-STING pathway chemically reduced interferon-β release and induced mitophagy also retarded release of the cytokine in response to LPS stimulation. Inhibition of VDAC1 mitigated IFN-β, as did the depletion of mitochondria in cells. Furthermore, the itaconate derivative 4-octyl itaconate reduced IFN-β induction in SSc monocytes, that was downstream of mitochondrial nucleic acid release. Fumarate, but not succinate was elevated in whole skin biopsies.</div></div><div><h3>Conclusion</h3><div>Fumarate metabolism links interferon release in SSc and may underlie the aberrant expression of interferon in SSc via cytosolic DNA released from mitochondria.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"117 2","pages":"Pages 30-35"},"PeriodicalIF":4.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018947","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}
Melanocytes protect the body from ultraviolet radiation by synthesizing melanin. Tyrosinase, a key enzyme in melanin production, accumulates in the endoplasmic reticulum (ER) during melanin synthesis, potentially causing ER stress. However, regulating ER function for melanin synthesis has been less studied than controlling Tyrosinase activity.
Objective
This study investigates the regulatory mechanisms of melanin production, focusing on ER stress and the ER stress-induced response.
Methods
B16 mouse melanoma cells induced to undergo melanogenesis were treated with unfolded protein response (UPR) inhibitors or chemical chaperones, and their effects on melanogenesis were analyzed.
Results
During melanogenesis in B16 cells stimulated by alpha-melanocyte-stimulating hormone (α-MSH), ER stress and UPR activation occurred, accompanied by increased Tyrosinase protein. Reducing IRE1 and ATF6 branch activity lowered melanin levels, while chemical chaperone treatment restored melanin production and increased Tyrosinase levels.
Conclusion
UPR activation, linked to elevated Tyrosinase levels, influences melanin production during melanogenesis. Modulating UPR can regulate melanin synthesis and provides a potential new approach for treating pigmentation disorders.
{"title":"Unfolded protein response modulates Tyrosinase levels and melanin production during melanogenesis","authors":"Akari Yamazaki , Issei Omura , Yasunao Kamikawa , Michihiro Hide , Akio Tanaka , Masayuki Kaneko , Kazunori Imaizumi , Atsushi Saito","doi":"10.1016/j.jdermsci.2025.01.001","DOIUrl":"10.1016/j.jdermsci.2025.01.001","url":null,"abstract":"<div><h3>Background</h3><div>Melanocytes protect the body from ultraviolet radiation by synthesizing melanin. Tyrosinase, a key enzyme in melanin production, accumulates in the endoplasmic reticulum (ER) during melanin synthesis, potentially causing ER stress. However, regulating ER function for melanin synthesis has been less studied than controlling Tyrosinase activity.</div></div><div><h3>Objective</h3><div>This study investigates the regulatory mechanisms of melanin production, focusing on ER stress and the ER stress-induced response.</div></div><div><h3>Methods</h3><div>B16 mouse melanoma cells induced to undergo melanogenesis were treated with unfolded protein response (UPR) inhibitors or chemical chaperones, and their effects on melanogenesis were analyzed.</div></div><div><h3>Results</h3><div>During melanogenesis in B16 cells stimulated by alpha-melanocyte-stimulating hormone (α-MSH), ER stress and UPR activation occurred, accompanied by increased Tyrosinase protein. Reducing IRE1 and ATF6 branch activity lowered melanin levels, while chemical chaperone treatment restored melanin production and increased Tyrosinase levels.</div></div><div><h3>Conclusion</h3><div>UPR activation, linked to elevated Tyrosinase levels, influences melanin production during melanogenesis. Modulating UPR can regulate melanin synthesis and provides a potential new approach for treating pigmentation disorders.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"117 2","pages":"Pages 36-44"},"PeriodicalIF":4.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143019036","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}
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