{"title":"Melanotransferrin (MELTF, MFI2, CD228) Expression Attenuates Malignant Melanoma Progression in the A375-Luc2 Murine Metastasis Model and Human Patients.","authors":"Jana Jandova, Georg T Wondrak","doi":"10.1016/j.jid.2024.05.028","DOIUrl":"10.1016/j.jid.2024.05.028","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":"2820-2823.e6"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141443999","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}
Ziao Zeng, Chella Krishna Vadivel, Maria Gluud, Martin R J Namini, Lang Yan, Sana Ahmad, Morten Bagge Hansen, Jonathan Coquet, Tomas Mustelin, Sergei B Koralov, Charlotte Menne Bonefeld, Anders Woetmann, Carsten Geisler, Emmanuella Guenova, Maria R Kamstrup, Thomas Litman, Lise-Mette R Gjerdrum, Terkild B Buus, Niels Ødum
{"title":"Keratinocytes Present Staphylococcus aureus Enterotoxins and Promote Malignant and Nonmalignant T Cell Proliferation in Cutaneous T-Cell Lymphoma.","authors":"Ziao Zeng, Chella Krishna Vadivel, Maria Gluud, Martin R J Namini, Lang Yan, Sana Ahmad, Morten Bagge Hansen, Jonathan Coquet, Tomas Mustelin, Sergei B Koralov, Charlotte Menne Bonefeld, Anders Woetmann, Carsten Geisler, Emmanuella Guenova, Maria R Kamstrup, Thomas Litman, Lise-Mette R Gjerdrum, Terkild B Buus, Niels Ødum","doi":"10.1016/j.jid.2024.04.018","DOIUrl":"10.1016/j.jid.2024.04.018","url":null,"abstract":"<p><p>Cutaneous T-cell lymphoma is characterized by malignant T cells proliferating in a unique tumor microenvironment dominated by keratinocytes (KCs). Skin colonization and infection by Staphylococcus aureus are a common cause of morbidity and are suspected of fueling disease activity. In this study, we show that expression of HLA-DRs, high-affinity receptors for staphylococcal enterotoxins (SEs), by KCs correlates with IFN-γ expression in the tumor microenvironment. Importantly, IFN-γ induces HLA-DR, SE binding, and SE presentation by KCs to malignant T cells from patients with Sézary syndrome and malignant and nonmalignant T-cell lines derived from patients with Sézary syndrome and mycosis fungoides. Likewise, preincubation of KCs with supernatant from patient-derived SE-producing S aureus triggers proliferation in malignant T cells and cytokine release (including IL-2), when cultured with nonmalignant T cells. This is inhibited by pretreatment with engineered bacteriophage S aureus-specific endolysins. Furthermore, alteration in the HLA-DR-binding sites of SE type A and small interfering RNA-mediated knockdown of Jak3 and IL-2Rγ block induction of malignant T-cell proliferation. In conclusion, we show that upon exposure to patient-derived S aureus and SE, KCs stimulate IL-2Rγ/Jak3-dependent proliferation of malignant and nonmalignant T cells in an environment with nonmalignant T cells. These findings suggest that KCs in the tumor microenvironment play a key role in S aureus-mediated disease activity in cutaneous T-cell lymphoma.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":"2789-2804.e10"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140961080","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}
Cristina Quílez, Luís B Bebiano, Eleri Jones, Uroš Maver, Luca Meesters, Piotr Parzymies, Emma Petiot, Gijs Rikken, Ignacio Risueño, Hamza Zaidi, Tanja Zidarič, Sander Bekeschus, Ellen H van den Bogaard, Matthew Caley, Helen Colley, Nuria Gago López, Sophia Letsiou, Christophe Marquette, Tina Maver, Rúben F Pereira, Desmond J Tobin, Diego Velasco
{"title":"Targeting the Complexity of In Vitro Skin Models: A Review of Cutting-Edge Developments.","authors":"Cristina Quílez, Luís B Bebiano, Eleri Jones, Uroš Maver, Luca Meesters, Piotr Parzymies, Emma Petiot, Gijs Rikken, Ignacio Risueño, Hamza Zaidi, Tanja Zidarič, Sander Bekeschus, Ellen H van den Bogaard, Matthew Caley, Helen Colley, Nuria Gago López, Sophia Letsiou, Christophe Marquette, Tina Maver, Rúben F Pereira, Desmond J Tobin, Diego Velasco","doi":"10.1016/j.jid.2024.04.032","DOIUrl":"10.1016/j.jid.2024.04.032","url":null,"abstract":"<p><p>Skin in vitro models offer much promise for research, testing drugs, cosmetics, and medical devices, reducing animal testing and extensive clinical trials. There are several in vitro approaches to mimicking human skin behavior, ranging from simple cell monolayer to complex organotypic and bioengineered 3-dimensional models. Some have been approved for preclinical studies in cosmetics, pharmaceuticals, and chemicals. However, development of physiologically reliable in vitro human skin models remains in its infancy. This review reports on advances in in vitro complex skin models to study skin homeostasis, aging, and skin disease.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":"2650-2670"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914985","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}
Min Jin Lee, Manel Ben Hammouda, Wanying Miao, Arinze E Okafor, Yingai J Jin, Huiying Sun, Vaibhav Jain, Vadim Markovtsov, Yarui Diao, Simon G Gregory, Jennifer Y Zhang
{"title":"UBE2N Is Essential for Maintenance of Skin Homeostasis and Suppression of Inflammation.","authors":"Min Jin Lee, Manel Ben Hammouda, Wanying Miao, Arinze E Okafor, Yingai J Jin, Huiying Sun, Vaibhav Jain, Vadim Markovtsov, Yarui Diao, Simon G Gregory, Jennifer Y Zhang","doi":"10.1016/j.jid.2024.04.017","DOIUrl":"10.1016/j.jid.2024.04.017","url":null,"abstract":"<p><p>UBE2N, a Lys63 ubiquitin-conjugating enzyme, plays critical roles in embryogenesis and immune system development and function. However, its roles in adult epithelial tissue homeostasis and pathogenesis are unclear. We generated conditional mouse models that deleted Ube2n in skin cells in a temporally and spatially controlled manner. We found that Ube2n knockout in the adult skin keratinocytes induced a range of inflammatory skin defects characteristic of psoriatic and actinic keratosis. These included inflammation, epidermal and dermal thickening, parakeratosis, and increased immune cell infiltration as well as signs of edema and blistering. Single-cell transcriptomic analyses and RT-qPCR showed that Ube2n-knockout keratinocytes expressed elevated myeloid cell chemoattractants such as Cxcl1 and Cxcl2 and decreased the homeostatic T lymphocyte chemoattractant Ccl27a. Consistently, the infiltrating immune cells were predominantly myeloid-derived cells, including neutrophils and M1-like macrophages, which expressed high levels of inflammatory cytokines such as Il1β and Il24. Pharmacological blockade of the IL-1 receptor associated kinases (IRAK1/4) alleviated inflammation, epidermal and dermal thickening, and immune infiltration of the Ube2n-mutant skin. Together, these findings highlight a key role of keratinocyte UBE2N in maintenance of epidermal homeostasis and skin immunity and identify IRAK1/4 as potential therapeutic target for inflammatory skin disorders.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":"2742-2753"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11581932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156044","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}
{"title":"Mpox: A Rising Threat-2 Public Health Emergencies in 2 Years.","authors":"Aditya K Gupta, Mesbah Talukder, Vincent Piguet","doi":"10.1016/j.jid.2024.09.004","DOIUrl":"10.1016/j.jid.2024.09.004","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":"2623-2627"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484779","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}
Shan Xiong, Fengjie Liu, Jingru Sun, Shuaixin Gao, Catherine C L Wong, Ping Tu, Yang Wang
{"title":"Abrogation of USP9X Is a Potential Strategy to Decrease PEG10 Levels and Impede Tumor Progression in Cutaneous T-Cell Lymphoma.","authors":"Shan Xiong, Fengjie Liu, Jingru Sun, Shuaixin Gao, Catherine C L Wong, Ping Tu, Yang Wang","doi":"10.1016/j.jid.2024.02.039","DOIUrl":"10.1016/j.jid.2024.02.039","url":null,"abstract":"<p><p>Advanced-stage cutaneous T-cell lymphomas (CTCLs) are notorious for their highly aggressive behavior, resistance to conventional treatments, and poor prognosis, particularly when large-cell transformation occurs. PEG10 has been recently proposed as a potent driver for large-cell transformation in CTCL. However, the targeting of PEG10 continues to present a formidable clinical challenge that has yet to be addressed. In this study, we report an important post-translational regulatory mechanism of PEG10 in CTCL. USP9X, a deubiquitinase, interacted with and deubiquitinated PEG10, thereby stabilizing PEG10. Knockdown of USP9X or pharmacological targeting of USP9X resulted in a prominent downregulation of PEG10 and its downstream pathway in CTCL. Moreover, USP9X inhibition conferred tumor cell growth disadvantage and enhanced apoptosis in vitro, an effect that occurred in part through its regulation on PEG10. Furthermore, we demonstrated that inhibition of USP9X obviously restrained CTCL tumor growth in vivo and that high expression of USP9X is associated with poor survival in patients with CTCL. Collectively, our findings uncover USP9X as a key post-translational regulator in the stabilization of PEG10 and suggest that targeting PEG10 stabilization through USP9X inhibition may represent a promising therapeutic strategy for advanced-stage CTCL.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":"2778-2788.e9"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857716","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}
Sripriya Murthy, Sabrina Patzelt, Axel Künstner, Hauke Busch, Enno Schmidt, Christian D Sadik
{"title":"Intravenous Ig Ameliorates Disease in a Murine Model of Anti-Laminin 332 Mucous Membrane Pemphigoid.","authors":"Sripriya Murthy, Sabrina Patzelt, Axel Künstner, Hauke Busch, Enno Schmidt, Christian D Sadik","doi":"10.1016/j.jid.2024.02.038","DOIUrl":"10.1016/j.jid.2024.02.038","url":null,"abstract":"<p><p>Intravenous Ig (IVIg) is used to treat mucous membrane pemphigoid, although its therapeutic effectivity is not sufficiently supported by randomized controlled clinical trials, and its mode of action is only insufficiently understood. We have examined the effect of IVIg in a mouse model of anti-laminin 332 mucous membrane pemphigoid and found that IVIg ameliorates both cutaneous and mucosal inflammatory lesions. Our investigation into the modes of action of IVIg in mucous membrane pemphigoid indicated effective anti-inflammatory mechanisms beyond the enhanced degradation of IgG mediated through inhibition of the FcRn. Our results suggest that IVIg curbs the activation of neutrophils at several levels. This includes a direct, immediate inhibitory effect on neutrophil activation by immune complexes but not C5a, which blunts the release of ROS and leukotriene B<sub>4</sub> from neutrophils. IVIg also suppresses the formation of neutrophil extracellular traps in response to calcium ion ionophore. In vivo treatment with IVIg altered the transcriptome of blood leukocytes and bone marrow neutrophils toward less proinflammatory phenotypes. Collectively, our results support the effectivity of IVIg in the treatment of mucous membrane pemphigoid and indicate that effects on neutrophils at multiple levels may significantly contribute to its therapeutic effects.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":"2671-2681.e1"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140871018","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}
Zhongya Song, Meng Gao, Tianxiao Li, Yi Zhang, Zhiming Chen, Linghan Hu, Juan Liu, Yingshi Li, Xi Wang, Yihe Liu, Ran Mo, Ruiyu Xiang, Di Hua, Hao Chen, Ming Zhao, Xu Chen, Xu Yao, Yong Yang
{"title":"TRPV3-Activated PARP1/AIFM1/MIF Axis through Oxidative Stress Contributes to Atopic Dermatitis.","authors":"Zhongya Song, Meng Gao, Tianxiao Li, Yi Zhang, Zhiming Chen, Linghan Hu, Juan Liu, Yingshi Li, Xi Wang, Yihe Liu, Ran Mo, Ruiyu Xiang, Di Hua, Hao Chen, Ming Zhao, Xu Chen, Xu Yao, Yong Yang","doi":"10.1016/j.jid.2024.04.020","DOIUrl":"10.1016/j.jid.2024.04.020","url":null,"abstract":"<p><p>TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3<sup>+/G568V</sup> mice, both of which carry gain-of-function variants in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. In this study, we showed that gain-of-function variant or pharmacological activation of TRPV3 resulted in poly(ADP-ribose) polymerase 1 (PARP1)/AIFM1/macrophage migration inhibitory factor axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging ROS, or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3<sup>+/G568V</sup> mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis, whereas inhibiting PARP1 largely alleviated the MC903-induced dermatitis. In addition, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of atopic dermatitis. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/macrophage migration inhibitory factor axis is a critical contributor to the pathogenesis of Olmsted syndrome and atopic dermatitis, suggesting that modulating the PARP1/AIFM1/macrophage migration inhibitory factor axis is a promising therapy for these conditions.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":"2695-2705.e8"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141187193","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":"Mouse Models of Itch.","authors":"Daniel Yassky, Brian S Kim","doi":"10.1016/j.jid.2024.08.018","DOIUrl":"10.1016/j.jid.2024.08.018","url":null,"abstract":"<p><p>Murine models are vital preclinical and biological tools for studying itch. In this paper, we explore how these models have enhanced our understanding of the mechanisms underlying itch through both acute and chronic itch models. We provide detailed protocols and recommend experimental setups for specific models to guide researchers in conducting itch research. We distinguish between what constitutes a bona fide pruritogen versus a stimulus that causes pruritogen release, an acute itch model versus a chronic itch model, and how murine models can capture aspects of pruritus in human disease. Finally, we highlight how mouse models of itch have transformed our understanding and development of therapeutics for chronic pruritus in patients.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":"2634-2644"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335601","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}