Pub Date : 2024-09-24DOI: 10.1016/j.jid.2024.09.005
Irene Soler-Sáez, Alcida Karz, Marta R Hidalgo, Borja Gómez-Cabañes, Adolfo López-Cerdán, José F Català-Senent, Kylie Prutisto-Chang, Nicole M Eskow, Benjamin Izar, Torben Redmer, Swaminathan Kumar, Michael A Davies, María de la Iglesia-Vayá, Eva Hernando, Francisco García-García
Melanoma represents a critical clinical challenge owing to its unfavorable outcomes. This type of skin cancer exhibits unique adaptability to the brain microenvironment, but its underlying molecular mechanisms are poorly understood. Recent findings have suggested that melanoma brain metastases may share biological processes similar to those found in various neurodegenerative diseases. To further characterize melanoma brain metastasis development, we explore the relationship between the transcriptional profiles of melanoma brain metastases and the neurodegenerative diseases Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We take an in silico approach to unveil a neurodegenerative signature of melanoma brain metastases compared with those of melanoma nonbrain metastasis (53 dysregulated genes were enriched in 11 functional terms, such as associated terms to the extracellular matrix and development) and with those of nontumor-bearing brain controls (195 dysregulated genes, mostly involved in development and cell differentiation, chromatin remodeling and nucleosome organization, and translation). Two genes, ITGA10 and DNAJC6, emerged as key potential markers being dysregulated in both scenarios. Finally, we developed an open-source, user-friendly web tool (https://bioinfo.cipf.es/metafun-mbm/) that allows interactive exploration of the complete results.
{"title":"Unveiling Common Transcriptomic Features between Melanoma Brain Metastases and Neurodegenerative Diseases.","authors":"Irene Soler-Sáez, Alcida Karz, Marta R Hidalgo, Borja Gómez-Cabañes, Adolfo López-Cerdán, José F Català-Senent, Kylie Prutisto-Chang, Nicole M Eskow, Benjamin Izar, Torben Redmer, Swaminathan Kumar, Michael A Davies, María de la Iglesia-Vayá, Eva Hernando, Francisco García-García","doi":"10.1016/j.jid.2024.09.005","DOIUrl":"10.1016/j.jid.2024.09.005","url":null,"abstract":"<p><p>Melanoma represents a critical clinical challenge owing to its unfavorable outcomes. This type of skin cancer exhibits unique adaptability to the brain microenvironment, but its underlying molecular mechanisms are poorly understood. Recent findings have suggested that melanoma brain metastases may share biological processes similar to those found in various neurodegenerative diseases. To further characterize melanoma brain metastasis development, we explore the relationship between the transcriptional profiles of melanoma brain metastases and the neurodegenerative diseases Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We take an in silico approach to unveil a neurodegenerative signature of melanoma brain metastases compared with those of melanoma nonbrain metastasis (53 dysregulated genes were enriched in 11 functional terms, such as associated terms to the extracellular matrix and development) and with those of nontumor-bearing brain controls (195 dysregulated genes, mostly involved in development and cell differentiation, chromatin remodeling and nucleosome organization, and translation). Two genes, ITGA10 and DNAJC6, emerged as key potential markers being dysregulated in both scenarios. Finally, we developed an open-source, user-friendly web tool (https://bioinfo.cipf.es/metafun-mbm/) that allows interactive exploration of the complete results.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335606","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 : 2024-09-23DOI: 10.1016/j.jid.2024.08.004
Manuela Pigors, Stephanie Goletz, Yao Wang, Shirin Emtenani, Christoph M Hammers, Maike M Holtsche, Sabrina Patzelt, Bianca Opelka, Felix H Stang, Inke R König, Christiane Radzimski, Lars Komorowski, Monique Aumailley, Cristina Has, Enno Schmidt
Laminin β4 was recently identified as a structural component of the dermal-epidermal junction and autoantigen of anti-p200 pemphigoid. In this study, we provided further evidence of the pathogenic effect of anti-laminin β4 IgG and identified potential binding partners of laminin β4. We showed that laminin β4 immune complexes led to activation of normal leukocytes and dose-dependent ROS release. Using cryosections of normal skin, we demonstrated that anti-laminin β4 patient serum IgG but not anti-laminin γ1 IgG, which are also detectable in patients with anti-p200 pemphigoid, cause dermal-epidermal separation in the presence of leukocytes. Proximity ligation assay and indirect immunofluorescence staining suggested that laminin β4 localizes closely to laminin α3 and γ2 in primary keratinocytes. Subsequent coimmunoprecipitation experiments using epidermal extracts confirmed the interaction of laminin β4 with the α3 and γ2 chains and indicated additional affinity to laminin γ1. The laminin β4-α3/β4-γ1 protein complexes were also detected using mass spectrometry. In conclusion, this study showed that anti-laminin β4 IgG can exert tissue damage in the skin, supporting their pathogenic role in anti-p200 pemphigoid. Our data further provide strong evidence for an interaction of laminin β4 with laminin α3, whereas its association to the laminin γ1 and γ2 chains is ambiguous.
{"title":"Anti-Laminin β4 IgG Drives Tissue Damage in Anti-p200 Pemphigoid and Shows Interactions with Laminin α3 and γ1/2 Chains.","authors":"Manuela Pigors, Stephanie Goletz, Yao Wang, Shirin Emtenani, Christoph M Hammers, Maike M Holtsche, Sabrina Patzelt, Bianca Opelka, Felix H Stang, Inke R König, Christiane Radzimski, Lars Komorowski, Monique Aumailley, Cristina Has, Enno Schmidt","doi":"10.1016/j.jid.2024.08.004","DOIUrl":"https://doi.org/10.1016/j.jid.2024.08.004","url":null,"abstract":"<p><p>Laminin β4 was recently identified as a structural component of the dermal-epidermal junction and autoantigen of anti-p200 pemphigoid. In this study, we provided further evidence of the pathogenic effect of anti-laminin β4 IgG and identified potential binding partners of laminin β4. We showed that laminin β4 immune complexes led to activation of normal leukocytes and dose-dependent ROS release. Using cryosections of normal skin, we demonstrated that anti-laminin β4 patient serum IgG but not anti-laminin γ1 IgG, which are also detectable in patients with anti-p200 pemphigoid, cause dermal-epidermal separation in the presence of leukocytes. Proximity ligation assay and indirect immunofluorescence staining suggested that laminin β4 localizes closely to laminin α3 and γ2 in primary keratinocytes. Subsequent coimmunoprecipitation experiments using epidermal extracts confirmed the interaction of laminin β4 with the α3 and γ2 chains and indicated additional affinity to laminin γ1. The laminin β4-α3/β4-γ1 protein complexes were also detected using mass spectrometry. In conclusion, this study showed that anti-laminin β4 IgG can exert tissue damage in the skin, supporting their pathogenic role in anti-p200 pemphigoid. Our data further provide strong evidence for an interaction of laminin β4 with laminin α3, whereas its association to the laminin γ1 and γ2 chains is ambiguous.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335595","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 : 2024-09-23DOI: 10.1016/j.jid.2024.08.015
Marie Beylot-Barry, Delphine Staumont-Salle
{"title":"Cutaneous T-Cell Lymphoma and Dupilumab Use: A Multifactorial and Complex Story.","authors":"Marie Beylot-Barry, Delphine Staumont-Salle","doi":"10.1016/j.jid.2024.08.015","DOIUrl":"https://doi.org/10.1016/j.jid.2024.08.015","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335597","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 : 2024-09-20DOI: 10.1016/j.jid.2024.07.031
Yoshiaki Matsushima, Sam T Hwang, Scott I Simon
{"title":"The Skinny on Dermal Fat and Its Anti-Inflammatory Role in Psoriasis.","authors":"Yoshiaki Matsushima, Sam T Hwang, Scott I Simon","doi":"10.1016/j.jid.2024.07.031","DOIUrl":"https://doi.org/10.1016/j.jid.2024.07.031","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305327","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 : 2024-09-20DOI: 10.1016/j.jid.2024.08.009
Yingzi Liu, Bogi Andersen, Johann E Gudjonsson, Maksim V Plikus
{"title":"Ancestral Diversity of Skin Reaches Single-Cell Resolution.","authors":"Yingzi Liu, Bogi Andersen, Johann E Gudjonsson, Maksim V Plikus","doi":"10.1016/j.jid.2024.08.009","DOIUrl":"https://doi.org/10.1016/j.jid.2024.08.009","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305317","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 : 2024-09-19DOI: 10.1016/j.jid.2024.08.027
Huizhen Chen, Yu Chen, Yi Zhou, Shensong Cao, Jing Lu, Lianyi Han, Thomas Worzfeld, Jean Krutmann, Jiucun Wang, Jingjing Xia
Characterizing the metabolite fingerprint from the skin surface provides invaluable insights into skin biology and microbe-host interactions. To ensure data accuracy and reproducibility, it is essential to develop standard operating procedures for skin surface metabolomics. However, there is a notable lack of studies in this area. In this study, we thoroughly evaluated different sampling materials, extraction solvents, taping methods (frequency and number of tapes), and analytical techniques to optimize skin surface metabolomics. Our results showed that the combination of D-Squame D100 tape with a methyl tert-butyl ether/methanol extractant is optimal for skin surface lipidomics. Performing the skin-taping procedure 5 times with 1 tape yields sufficient biomass for lipid analysis, whereas the optimal taping procedure varies for water-soluble compounds. In addition, our study identified associations among the skin surface metabolites, some of which potentially underlie the formation of microbial cutotypes and offer insights into host-microbe interactions.
{"title":"Optimizing Skin Surface Metabolomics: A Comprehensive Evaluation of Sampling Methods, Extraction Solvents, and Analytical Techniques.","authors":"Huizhen Chen, Yu Chen, Yi Zhou, Shensong Cao, Jing Lu, Lianyi Han, Thomas Worzfeld, Jean Krutmann, Jiucun Wang, Jingjing Xia","doi":"10.1016/j.jid.2024.08.027","DOIUrl":"10.1016/j.jid.2024.08.027","url":null,"abstract":"<p><p>Characterizing the metabolite fingerprint from the skin surface provides invaluable insights into skin biology and microbe-host interactions. To ensure data accuracy and reproducibility, it is essential to develop standard operating procedures for skin surface metabolomics. However, there is a notable lack of studies in this area. In this study, we thoroughly evaluated different sampling materials, extraction solvents, taping methods (frequency and number of tapes), and analytical techniques to optimize skin surface metabolomics. Our results showed that the combination of D-Squame D100 tape with a methyl tert-butyl ether/methanol extractant is optimal for skin surface lipidomics. Performing the skin-taping procedure 5 times with 1 tape yields sufficient biomass for lipid analysis, whereas the optimal taping procedure varies for water-soluble compounds. In addition, our study identified associations among the skin surface metabolites, some of which potentially underlie the formation of microbial cutotypes and offer insights into host-microbe interactions.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305323","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 : 2024-09-19DOI: 10.1016/j.jid.2024.08.024
Myriam Cassagne, Stéphane Galiacy, Anna Kychygina, Eric Chapotot, Martin Wallaert, Bertrand Vabres, Marie Tauber, Sébastien Barbarot, Carle Paul, Pierre Fournié, Michel Simon
Dupilumab has demonstrated efficacy in the treatment of atopic dermatitis. However, a subset of patients experiences ocular adverse events (OAEs), including conjunctivitis and dry eye syndrome, the pathological mechanisms of which are still unknown. In a bicentric study, we used DNA microarray analysis to compare the transcriptome of conjunctival cells of patients with atopic dermatitis collected by impression cytology before (M0) and 4 months after (M4) initiating dupilumab treatment. Thirty-six patients were included and divided in 2 groups according to their ophthalmological status at M4: 12 with OAEs (OAE+) and 24 without (OAE-). The analysis revealed 52 differentially expressed genes between OAE+ and OAE- patients at M0 and 113 at M4. Ingenuity Pathway Analysis enrichment revealed a psoriasis signature in OAE+ patients, both before and after OAE outcomes. In addition, we noticed the overexpression of several genes involved in keratinocyte differentiation, particularly encoding cornified envelope components. Among the 16 differentially expressed genes selected for real-time RT-PCR validation, 9 were confirmed as upregulated at M4 in OAE+ versus OAE- patients, validating the psoriasis signature, whereas MUC7 was downregulated. In conclusion, these results suggest that a conjunctival transcriptomic profile predisposes some patients with atopic dermatitis to developing OAEs upon dupilumab treatment.
{"title":"Superficial Conjunctival Cells from Dupilumab-Treated Patients with Atopic Dermatitis with Ocular Adverse Events Display a Transcriptomic Psoriasis Signature.","authors":"Myriam Cassagne, Stéphane Galiacy, Anna Kychygina, Eric Chapotot, Martin Wallaert, Bertrand Vabres, Marie Tauber, Sébastien Barbarot, Carle Paul, Pierre Fournié, Michel Simon","doi":"10.1016/j.jid.2024.08.024","DOIUrl":"10.1016/j.jid.2024.08.024","url":null,"abstract":"<p><p>Dupilumab has demonstrated efficacy in the treatment of atopic dermatitis. However, a subset of patients experiences ocular adverse events (OAEs), including conjunctivitis and dry eye syndrome, the pathological mechanisms of which are still unknown. In a bicentric study, we used DNA microarray analysis to compare the transcriptome of conjunctival cells of patients with atopic dermatitis collected by impression cytology before (M0) and 4 months after (M4) initiating dupilumab treatment. Thirty-six patients were included and divided in 2 groups according to their ophthalmological status at M4: 12 with OAEs (OAE+) and 24 without (OAE-). The analysis revealed 52 differentially expressed genes between OAE+ and OAE- patients at M0 and 113 at M4. Ingenuity Pathway Analysis enrichment revealed a psoriasis signature in OAE+ patients, both before and after OAE outcomes. In addition, we noticed the overexpression of several genes involved in keratinocyte differentiation, particularly encoding cornified envelope components. Among the 16 differentially expressed genes selected for real-time RT-PCR validation, 9 were confirmed as upregulated at M4 in OAE+ versus OAE- patients, validating the psoriasis signature, whereas MUC7 was downregulated. In conclusion, these results suggest that a conjunctival transcriptomic profile predisposes some patients with atopic dermatitis to developing OAEs upon dupilumab treatment.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305326","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 : 2024-09-19DOI: 10.1016/j.jid.2024.08.028
Yuki Saito, Roberta Lotti, Haruna Kimura, Akito Hasegawa, Brydon Bennett, Antonino Amato, Carlo Pincelli, Riichiro Abe
{"title":"Advancements in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Treatment: Utilizing Fas-FasL Inhibition to Target Cell Death Signaling Pathways for Practical Human Application.","authors":"Yuki Saito, Roberta Lotti, Haruna Kimura, Akito Hasegawa, Brydon Bennett, Antonino Amato, Carlo Pincelli, Riichiro Abe","doi":"10.1016/j.jid.2024.08.028","DOIUrl":"10.1016/j.jid.2024.08.028","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305316","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 : 2024-09-19DOI: 10.1016/j.jid.2024.07.036
Thom Doeleman, Siemen Brussee, Liesbeth M Hondelink, Daniëlle W F Westerbeek, Ana M Sequeira, Pieter A Valkema, Patty M Jansen, Junling He, Maarten H Vermeer, Koen D Quint, Marijke R van Dijk, Fons J Verbeek, Jesper Kers, Anne M R Schrader
The diagnosis of early-stage mycosis fungoides (MF) is challenging owing to shared clinical and histopathological features with benign inflammatory dermatoses. Recent evidence has shown that deep learning (DL) can assist pathologists in cancer classification, but this field is largely unexplored for cutaneous lymphomas. This study evaluates DL in distinguishing early-stage MF from benign inflammatory dermatoses using a unique dataset of 924 H&E-stained whole-slide images from skin biopsies, including 233 patients with early-stage MF and 353 patients with benign inflammatory dermatoses. All patients with MF were diagnosed after clinicopathological correlation. The classification accuracy of weakly supervised DL models was benchmarked against 3 expert pathologists. The highest performance on a temporal test set was at ×200 magnification (0.50 μm per pixel resolution), with a mean area under the curve of 0.827 ± 0.044 and a mean balanced accuracy of 76.2 ± 3.9%. This nearly matched the 77.7% mean balanced accuracy of the 3 expert pathologists. Most (63.5%) attention heatmaps corresponded well with the pathologists' region of interest. Considering the difficulty of the MF versus benign inflammatory dermatoses classification task, the results of this study show promise for future applications of weakly supervised DL in diagnosing early-stage MF. Achieving clinical-grade performance will require larger multi-institutional datasets and improved methodologies, such as multimodal DL with incorporation of clinical data.
{"title":"Deep Learning-Based Classification of Early-Stage Mycosis Fungoides and Benign Inflammatory Dermatoses on H&E-Stained Whole-Slide Images: A Retrospective, Proof-of-Concept Study.","authors":"Thom Doeleman, Siemen Brussee, Liesbeth M Hondelink, Daniëlle W F Westerbeek, Ana M Sequeira, Pieter A Valkema, Patty M Jansen, Junling He, Maarten H Vermeer, Koen D Quint, Marijke R van Dijk, Fons J Verbeek, Jesper Kers, Anne M R Schrader","doi":"10.1016/j.jid.2024.07.036","DOIUrl":"10.1016/j.jid.2024.07.036","url":null,"abstract":"<p><p>The diagnosis of early-stage mycosis fungoides (MF) is challenging owing to shared clinical and histopathological features with benign inflammatory dermatoses. Recent evidence has shown that deep learning (DL) can assist pathologists in cancer classification, but this field is largely unexplored for cutaneous lymphomas. This study evaluates DL in distinguishing early-stage MF from benign inflammatory dermatoses using a unique dataset of 924 H&E-stained whole-slide images from skin biopsies, including 233 patients with early-stage MF and 353 patients with benign inflammatory dermatoses. All patients with MF were diagnosed after clinicopathological correlation. The classification accuracy of weakly supervised DL models was benchmarked against 3 expert pathologists. The highest performance on a temporal test set was at ×200 magnification (0.50 μm per pixel resolution), with a mean area under the curve of 0.827 ± 0.044 and a mean balanced accuracy of 76.2 ± 3.9%. This nearly matched the 77.7% mean balanced accuracy of the 3 expert pathologists. Most (63.5%) attention heatmaps corresponded well with the pathologists' region of interest. Considering the difficulty of the MF versus benign inflammatory dermatoses classification task, the results of this study show promise for future applications of weakly supervised DL in diagnosing early-stage MF. Achieving clinical-grade performance will require larger multi-institutional datasets and improved methodologies, such as multimodal DL with incorporation of clinical data.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305320","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 : 2024-09-18DOI: 10.1016/j.jid.2024.08.023
Matilde V Neto, Michael J Hall, João Charneca, Cristina Escrevente, Miguel C Seabra, Duarte C Barral
In the skin, melanin is synthesized by melanocytes within melanosomes and transferred to keratinocytes. After being phagocytosed by keratinocytes, melanin polarizes to supranuclear caps that protect against the genotoxic effects of UVR. We provide evidence that melanin-containing phagosomes undergo a canonical maturation process, with the sequential acquisition of early and late endosomal markers. Subsequently, these phagosomes fuse with active lysosomes, leading to the formation of a melanin-containing phagolysosome that we named melanokerasome. Melanokerasomes achieve juxtanuclear positioning through lysosomal trafficking regulators Rab7 and RILP. Mature melanokerasomes exhibit lysosomal markers, elude connections with the endo/phagocytic pathway, are weakly degradative, retain undigested cargo, and are likely tethered to the nuclear membrane. We propose that they represent a lysosomal-derived storage compartment that has exited the lysosome cycle, akin to the formation of lipofuscin in aged cells and dysfunctional lysosomes in lysosomal storage and age-related diseases. This storage lysosome allows melanin to persist for long periods, where it can exert its photoprotective effect efficiently.
{"title":"Photoprotective Melanin Is Maintained within Keratinocytes in Storage Lysosomes.","authors":"Matilde V Neto, Michael J Hall, João Charneca, Cristina Escrevente, Miguel C Seabra, Duarte C Barral","doi":"10.1016/j.jid.2024.08.023","DOIUrl":"10.1016/j.jid.2024.08.023","url":null,"abstract":"<p><p>In the skin, melanin is synthesized by melanocytes within melanosomes and transferred to keratinocytes. After being phagocytosed by keratinocytes, melanin polarizes to supranuclear caps that protect against the genotoxic effects of UVR. We provide evidence that melanin-containing phagosomes undergo a canonical maturation process, with the sequential acquisition of early and late endosomal markers. Subsequently, these phagosomes fuse with active lysosomes, leading to the formation of a melanin-containing phagolysosome that we named melanokerasome. Melanokerasomes achieve juxtanuclear positioning through lysosomal trafficking regulators Rab7 and RILP. Mature melanokerasomes exhibit lysosomal markers, elude connections with the endo/phagocytic pathway, are weakly degradative, retain undigested cargo, and are likely tethered to the nuclear membrane. We propose that they represent a lysosomal-derived storage compartment that has exited the lysosome cycle, akin to the formation of lipofuscin in aged cells and dysfunctional lysosomes in lysosomal storage and age-related diseases. This storage lysosome allows melanin to persist for long periods, where it can exert its photoprotective effect efficiently.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305324","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}