Su M Lwin, Shir Azrielant, Juan He, Christopher E M Griffiths
{"title":"Curing Psoriasis.","authors":"Su M Lwin, Shir Azrielant, Juan He, Christopher E M Griffiths","doi":"10.1016/j.jid.2024.09.012","DOIUrl":"10.1016/j.jid.2024.09.012","url":null,"abstract":"<p><p>As medicine advances, cures are being found for diseases that were previously considered incurable, as is the case for some types of cancer. Traditionally, the term cure is reserved for resolution of disease, both at a clinical and a molecular level, which continues after cessation of treatment. Biologic therapies have revolutionized the definition of remission in severe psoriasis, with some patients achieving long-lasting disease suppression, but the disease nearly always relapses on withdrawal of the drug. Our improved understanding of the pathomechanisms of psoriasis, coupled with anecdotal reports of long-term clearance of the disease after cell-based therapies, leads us to the hypothesis that psoriasis is curable. We propose that cure of psoriasis can be achieved by restoring immune homeostasis through a combinatorial, personalized medicine approach encompassing early intervention to include biologics, advanced therapeutics, and lifestyle modification.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":"2645-2649"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484777","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}
Andrew Blauvelt, Kenneth B Gordon, Richard G Langley, Patrick J Branigan, Yanqing Chen, Megan Miller, Chenglong Han, Steven Fakharzadeh, Ernesto J Muñoz-Elías, April W Armstrong
{"title":"Residual Lesional Gene Expression in Psoriasis Patients with Complete Skin Clearance Treated with Guselkumab or Adalimumab in VOYAGE 1 and 2.","authors":"Andrew Blauvelt, Kenneth B Gordon, Richard G Langley, Patrick J Branigan, Yanqing Chen, Megan Miller, Chenglong Han, Steven Fakharzadeh, Ernesto J Muñoz-Elías, April W Armstrong","doi":"10.1016/j.jid.2024.05.020","DOIUrl":"10.1016/j.jid.2024.05.020","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":"2816-2819.e2"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474242","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}
Xin Tong, Hope E Burks, Ziyou Ren, Jennifer L Koetsier, Quinn R Roth-Carter, Kathleen J Green
{"title":"Crosstalk in Skin: Loss of Desmoglein 1 in Keratinocytes Inhibits BRAF<sup>V600E</sup>-induced Cellular Senescence in Human Melanocytes.","authors":"Xin Tong, Hope E Burks, Ziyou Ren, Jennifer L Koetsier, Quinn R Roth-Carter, Kathleen J Green","doi":"10.1016/j.jid.2024.10.608","DOIUrl":"10.1016/j.jid.2024.10.608","url":null,"abstract":"<p><p>Melanoma arises from transformation of melanocytes in the basal layer of epidermis where they are surrounded by keratinocytes, with which they interact through cell contact and paracrine communication. Although research focuses on how the accumulation of oncogene and tumor suppressor gene mutations in melanocytes drive melanomagenesis, how alterations in keratinocytes serve as extrinsic drivers of melanoma initiation and progression is poorly understood. We recently identified keratinocyte desmoglein 1 (Dsg1) as an mediator of keratinocyte:melanoma crosstalk. Here we address the extent to which Dsg1 loss, which occurs in response to environmental stress such as ultraviolet radiation, affects early steps in melanomagenesis. RNA-Seq analysis revealed that paracrine signals from Dsg1-deficient keratinocytes mediate a transcriptional switch from a differentiated to undifferentiated cell state in melanocytes expressing BRAF<sup>V600E</sup>. Of 221 differentially expressed genes in BRAF<sup>V600E</sup> cells treated with conditioned media (CM) from Dsg1-deficient keratinocytes the laminin superfamily member NTN4/Netrin-4, which inhibits senescence, stood out. Indeed, while BRAF<sup>V600E</sup> melanocytes treated with CM from Dsg1-deficient keratinocytes showed signs of senescence bypass, NTN4 knockdown reversed, while ectopic NTN4 expression mimicked, these effects. These results suggest that Dsg1 loss in keratinocytes provides an extrinsic signal to push melanocytes towards oncogenic transformation once an initial mutation has been introduced.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142712334","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}
Veronica M Amuso, MaryEllen R Haas, Paula O Cooper, Ranojoy Chatterjee, Sana Hafiz, Shatha Salameh, Chiraag Gohel, Miguel F Mazumder, Violet Josephson, Sarah S Kleb, Khatereh Khorsandi, Anelia Horvath, Ali Rahnavard, Brett A Shook
{"title":"Fibroblast-mediated macrophage recruitment supports acute wound healing.","authors":"Veronica M Amuso, MaryEllen R Haas, Paula O Cooper, Ranojoy Chatterjee, Sana Hafiz, Shatha Salameh, Chiraag Gohel, Miguel F Mazumder, Violet Josephson, Sarah S Kleb, Khatereh Khorsandi, Anelia Horvath, Ali Rahnavard, Brett A Shook","doi":"10.1016/j.jid.2024.10.609","DOIUrl":"10.1016/j.jid.2024.10.609","url":null,"abstract":"<p><p>Epithelial and immune cells have long been appreciated for their contribution to the early immune response after injury; however, much less is known about the role of mesenchymal cells. Using single nuclei RNA-sequencing, we defined changes in gene expression associated with inflammation at 1-day post-wounding (dpw) in mouse skin. Compared to keratinocytes and myeloid cells, we detected enriched expression of pro-inflammatory genes in fibroblasts associated with deeper layers of the skin. In particular, SCA1+ fibroblasts were enriched for numerous chemokines, including CCL2, CCL7, and IL33 compared to SCA1- fibroblasts. Genetic deletion of Ccl2 in fibroblasts resulted in fewer wound bed macrophages and monocytes during injury-induced inflammation with reduced revascularization and re-epithelialization during the proliferation phase of healing. These findings highlight the important contribution of fibroblast-derived factors to injury-induced inflammation and the impact of immune cell dysregulation on subsequent tissue repair.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142712336","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}
Julia Boix, Jana Knuever, Nadine Niehoff, Ayesha Sen, David Pla-Martin, Olivier R Baris, Julia Etich, Bent Brachvogel, Harshita Kaul, Dirk Isbrandt, Ekaterina Soroka, Hisham Bazzi, Roland H Wenger, Patrick Giavalisco, Rudolf J Wiesner
{"title":"Constitutive HIF-1α expression in the epidermis fuels proliferation and is essential for effective barrier formation.","authors":"Julia Boix, Jana Knuever, Nadine Niehoff, Ayesha Sen, David Pla-Martin, Olivier R Baris, Julia Etich, Bent Brachvogel, Harshita Kaul, Dirk Isbrandt, Ekaterina Soroka, Hisham Bazzi, Roland H Wenger, Patrick Giavalisco, Rudolf J Wiesner","doi":"10.1016/j.jid.2024.09.022","DOIUrl":"https://doi.org/10.1016/j.jid.2024.09.022","url":null,"abstract":"<p><p>Epidermis is one of the most rapidly proliferating tissues in the body with high demands for ATP and cellular building blocks. Here we show that, in order to meet these requirements, keratinocytes constitutively express hypoxia-inducible factor-1α (HIF-1α), even in the presence of oxygen levels sufficient for HIF-1α hydroxylation. We previously reported that mice with severe epidermal mitochondrial dysfunction actually showed a hyperproliferative epidermis, but rapidly died of systemic lactic acidosis and hypoglycemia, indicating excessive glycolysis. In the present work, we interrogated HIF-1α function in glycolysis by its epidermal ablation combined with mitochondrial dysfunction, which resulted in decreased proliferation but even earlier lethality due to a severe barrier defect. Our data demonstrate that HIF-1α is indispensable for maintaining a high aerobic glycolytic flux necessary for supplying energy, but also for synthetizing cellular building blocks like lipids, which are both essential for proliferation as well as barrier formation. HIF-1α is stabilized in keratinocytes in the presence of oxygen by high levels of HIF-1α transcripts, low levels of prolyl-4-hydroxylases (PHD2 and 3) and a low cellular α-ketoglutarate/lactate ratio, likely inhibiting PHD activity. Our data suggest a key role for constitutive HIF-1α expression allowing a Warburg-like metabolism in healthy, highly proliferative keratinocytes, similar to tumour cells.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696291","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":"Skin-resident γδ T cells mediate potent and selective antitumor cytotoxicity through directed chemotactic migration and mobilization of cytotoxic granules.","authors":"Jiacai Yang, Zhihui Liu, Xiaohong Hu, Xiaorong Zhang, Yong Huang, Yunxia Chen, Cheng Chen, Ruoyu Shang, Yuanyang Tang, Wengang Hu, Jue Wang, Han-Ming Shen, Jun Hu, Weifeng He","doi":"10.1016/j.jid.2024.10.607","DOIUrl":"https://doi.org/10.1016/j.jid.2024.10.607","url":null,"abstract":"<p><p>Dendritic epidermal T cells (DETCs) are a unique subset of γδ T cells that reside predominantly in mouse epidermis, yet their antitumor functions remain enigmatic. Here we report that DETCs mediate potent and exquisitely selective cytotoxicity against diverse tumor types while sparing healthy cells. In vitro, DETCs induced apoptosis in melanoma, hepatoma, colon carcinoma and lymphoma lines in a dose- and time-dependent manner that required direct cell-cell contact. In vivo, adoptive DETC transfer significantly suppressed melanoma growth and metastasis while prolonging survival. Mechanistically, DETCs upregulated perforin/granzyme B expression upon tumor recognition, and inhibition of this pathway ablated cytotoxicity. DETCs selectively homed to and formed intimate contacts with tumor cells in vivo through directed chemotaxis and aggregation. Tumor engagement triggered pro-inflammatory DETC activation while dampening immunosuppressive factors in the microenvironment. Notably, mTOR signaling coupled tumor recognition to DETC trafficking, cytotoxicity and inflammatory programs, as rapamycin treatment impaired effector functions and therapeutic efficacy. Collectively, these findings establish DETCs as multidimensional antitumor effectors and provide insights for harnessing their unique biology for cancer immunotherapy.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142690200","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}
Zengyang Yu, Xinyi Tang, Zeyu Chen, Yifan Hu, Shuqin Zhang, Chunyuan Guo, Jun Gu, Yuling Shi, Yu Gong
{"title":"Role of ADAM10/17-mediated Cleavage of LAG3 in the Impairment of Immunosuppression in Psoriasis.","authors":"Zengyang Yu, Xinyi Tang, Zeyu Chen, Yifan Hu, Shuqin Zhang, Chunyuan Guo, Jun Gu, Yuling Shi, Yu Gong","doi":"10.1016/j.jid.2024.10.606","DOIUrl":"https://doi.org/10.1016/j.jid.2024.10.606","url":null,"abstract":"<p><p>Despite extensive research on immune activation regulatory mechanisms, studies on immune suppression in psoriasis are limited. LAG3, a newly identified immune checkpoint, plays a crucial role in modulating immune responses and maintaining T regulatory (Treg) cell function. However, its involvement in psoriasis is unclear. We show that psoriasis is associated with reduced LAG3 expression in CD4 T cells and Treg cells. Further analysis revealed that the decline in LAG3 levels was linked to ADAM10/17-mediated proteolytic cleavage, which was upregulated in psoriasis. Clinical utilization of the IL-17A antagonist secukinumab, along with the in-vivo and in-vitro IL-17A-induced models, supported the potential of IL-17A to induce ADAM10/17 expression and trigger LAG3 cleavage. Through the Jurkat cell model, IL-17A was found to regulate ADAM10/17 expression by activating FOXM1. Additionally, treatment with the ADAM10/17 inhibitor GW280264X showed ameliorative effects on psoriasis-like mouse models and lipopolysaccharide-induced inflammation. Collectively, the findings of this study uncover the immune regulatory role of the ADAM10/17-LAG3 axis in psoriasis and highlight the therapeutic potential of targeting ADAM10/17 for psoriasis treatment.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142690199","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}
B Seyran, I Avila, C Galvan, G Robles, C Murphy, H Christofk, W E Lowry
{"title":"Inhibition of pyruvate oxidation diminishes melanoma progression.","authors":"B Seyran, I Avila, C Galvan, G Robles, C Murphy, H Christofk, W E Lowry","doi":"10.1016/j.jid.2024.10.605","DOIUrl":"https://doi.org/10.1016/j.jid.2024.10.605","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684021","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":"Blood-borne bone marrow-derived epithelial cells searching for a niche: The Epithelial Transit Hypothesis.","authors":"Stephanie M Holtorf, Rebecca J Morris","doi":"10.1016/j.jid.2024.10.603","DOIUrl":"https://doi.org/10.1016/j.jid.2024.10.603","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684018","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}