Pub Date : 2024-08-08DOI: 10.1016/j.jid.2024.07.012
Christopher G O'Neill, Andrew P Sawaya, Spencer Mehdizadeh, Stephen R Brooks, Kowser Hasneen, Subhashree Nayak, Andrew M Overmiller, Maria I Morasso
{"title":"SOX2-Dependent Wound Repair Signature Triggers Prohealing Outcome in Hyperglycemic Wounds.","authors":"Christopher G O'Neill, Andrew P Sawaya, Spencer Mehdizadeh, Stephen R Brooks, Kowser Hasneen, Subhashree Nayak, Andrew M Overmiller, Maria I Morasso","doi":"10.1016/j.jid.2024.07.012","DOIUrl":"10.1016/j.jid.2024.07.012","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914983","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 : 2024-08-08DOI: 10.1016/j.jid.2024.07.017
Dahim Choi, Mojtaba Bakhtiari, William Pilcher, Chenbin Huang, Beena E Thomas, Hope Mumme, Gerardo Blanco, Ravi Rajani, Marcos C Schechter, Maya Fayfman, Gabriel Santamarina, Swati Bhasin, Manoj Bhasin
Diabetic foot ulcer (DFU) is a critical complication of diabetes, but the wound microenvironment and its healing process are not completely understood. In this study, we optimized single-cell profiling from sharp debrided ulcers. Our findings demonstrate that healing-DFUs were significantly enriched with distinct fibroblasts expressing genes related to inflammation (CHI3L1, IL6) and extracellular matrix remodeling (ASPN), validating our previous studies on surgically resected ulcers. The race-focused analysis depicted lower expression of key healing-associated genes such as CHIL3L1, MMP11, and SFRP4 in fibroblasts of non-Hispanic Black (NHB) patients compared to White patients. In cellular communication analysis, healing enriched fibroblasts of NHBs exhibited upregulation of signaling pathways such as WNT while those of White showed IGF and MK pathways upregulation. Our findings advocate race as a risk marker of DFU outcomes, likely reflecting underlying disparities in environmental exposures and access to care that profoundly influence healing markers. Using sharp debrided tissues for single-cell assays, this study highlights the need for in-depth investigations into dysregulated wound healing microenvironments of under-represented racial groups.
{"title":"Single-cell Analysis of Debrided Diabetic Foot Ulcers Reveals Dysregulated Wound Healing Environment in non-Hispanic Blacks.","authors":"Dahim Choi, Mojtaba Bakhtiari, William Pilcher, Chenbin Huang, Beena E Thomas, Hope Mumme, Gerardo Blanco, Ravi Rajani, Marcos C Schechter, Maya Fayfman, Gabriel Santamarina, Swati Bhasin, Manoj Bhasin","doi":"10.1016/j.jid.2024.07.017","DOIUrl":"https://doi.org/10.1016/j.jid.2024.07.017","url":null,"abstract":"<p><p>Diabetic foot ulcer (DFU) is a critical complication of diabetes, but the wound microenvironment and its healing process are not completely understood. In this study, we optimized single-cell profiling from sharp debrided ulcers. Our findings demonstrate that healing-DFUs were significantly enriched with distinct fibroblasts expressing genes related to inflammation (CHI3L1, IL6) and extracellular matrix remodeling (ASPN), validating our previous studies on surgically resected ulcers. The race-focused analysis depicted lower expression of key healing-associated genes such as CHIL3L1, MMP11, and SFRP4 in fibroblasts of non-Hispanic Black (NHB) patients compared to White patients. In cellular communication analysis, healing enriched fibroblasts of NHBs exhibited upregulation of signaling pathways such as WNT while those of White showed IGF and MK pathways upregulation. Our findings advocate race as a risk marker of DFU outcomes, likely reflecting underlying disparities in environmental exposures and access to care that profoundly influence healing markers. Using sharp debrided tissues for single-cell assays, this study highlights the need for in-depth investigations into dysregulated wound healing microenvironments of under-represented racial groups.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914982","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 : 2024-08-08DOI: 10.1016/j.jid.2024.07.021
Tae-Jong Kang, Sun Yeop Lee, Sanghyuk Yoon, Eun Gyo Kim, Jung Oh Kim, Jong-Seung Kim, Jin Park, Kyung-Hwa Nam
Lipid-lowering agents have been suggested as a therapeutic option for vitiligo on the basis of the potential pathogenic role of lipid metabolism abnormalities. We aimed to explore the impact of genetically proxied lipid-lowering agents on the risk of vitiligo and potentially associated mediators. GWAS summary statistics for European ancestry were extracted from the largest available meta-analysis for vitiligo: the Global Lipids Genetics Consortium for 7 lipid profiles and 2 large biobanks, UK Biobank and deCODE, for 4719 proteins. After identifying lipid-lowering agents with genetically proxied protective effects against vitiligo using lipid-lowering and protein-inhibition Mendelian randomization (MR) analyses, multivariable and 2-step MR analyses were conducted to identify potential mediators between lipid-lowering agents and vitiligo. Lipid-lowering MR indicated a potential role of PCSK9 in reducing the vitiligo risk (OR [95% confidence interval] = 0.71 [0.52-0.95]), which was replicated in PCSK9-inhibition MR analyses across 2 separate biobanks (UK Biobank: OR [95% confidence interval] = 0.82 [0.71-0.96]; deCODE: OR [95% confidence interval] = 0.78 [0.67-0.91]). Multivariable MR suggested that well-known lipid profiles do not mediate the relationship between PCSK9 and vitiligo, whereas 2-step MR analyses identified 5 potential protein mediators (CCN5, CXCL12, FCRL1, legumain, and FGF2). Hence, PCSK9 inhibitor may attenuate the vitiligo risk; PCSK9 and the potential protein mediators can serve as promising novel therapeutic targets for its effective treatment.
{"title":"PCSK9 Inhibitors and the Risk of Vitiligo: A Mendelian Randomization Study.","authors":"Tae-Jong Kang, Sun Yeop Lee, Sanghyuk Yoon, Eun Gyo Kim, Jung Oh Kim, Jong-Seung Kim, Jin Park, Kyung-Hwa Nam","doi":"10.1016/j.jid.2024.07.021","DOIUrl":"10.1016/j.jid.2024.07.021","url":null,"abstract":"<p><p>Lipid-lowering agents have been suggested as a therapeutic option for vitiligo on the basis of the potential pathogenic role of lipid metabolism abnormalities. We aimed to explore the impact of genetically proxied lipid-lowering agents on the risk of vitiligo and potentially associated mediators. GWAS summary statistics for European ancestry were extracted from the largest available meta-analysis for vitiligo: the Global Lipids Genetics Consortium for 7 lipid profiles and 2 large biobanks, UK Biobank and deCODE, for 4719 proteins. After identifying lipid-lowering agents with genetically proxied protective effects against vitiligo using lipid-lowering and protein-inhibition Mendelian randomization (MR) analyses, multivariable and 2-step MR analyses were conducted to identify potential mediators between lipid-lowering agents and vitiligo. Lipid-lowering MR indicated a potential role of PCSK9 in reducing the vitiligo risk (OR [95% confidence interval] = 0.71 [0.52-0.95]), which was replicated in PCSK9-inhibition MR analyses across 2 separate biobanks (UK Biobank: OR [95% confidence interval] = 0.82 [0.71-0.96]; deCODE: OR [95% confidence interval] = 0.78 [0.67-0.91]). Multivariable MR suggested that well-known lipid profiles do not mediate the relationship between PCSK9 and vitiligo, whereas 2-step MR analyses identified 5 potential protein mediators (CCN5, CXCL12, FCRL1, legumain, and FGF2). Hence, PCSK9 inhibitor may attenuate the vitiligo risk; PCSK9 and the potential protein mediators can serve as promising novel therapeutic targets for its effective treatment.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914981","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 : 2024-08-07DOI: 10.1016/j.jid.2024.07.010
Elvis B Kidzeru, Musalula Sinkala, Temwani Chalwa, Relebohile Matobole, Madeha Alkelani, Zeinab Ghasemishahrestani, Stanley K Mbandi, Jonathan Blackburn, David L Tabb, Henry Ademola Adeola, Nonhlanhla P Khumalo, Ardeshir Bayat
Keloid disease (KD) is a common connective tissue disorder of unknown aetiopathogenesis with ill-defined treatment. Keloid scars present as exophytic fibroproliferative reticular lesions postcutaneous injury, and even though KD remains neoplastically benign, keloid lesions behave locally aggressive, invasive and expansive. To date, there is limited understanding and validation of biomarkers identified through combined proteomic and genomic evaluation of KD. Therefore, the aim in this study was to identify putative causative candidates in KD by performing a comprehensive proteomics analysis of subcellular fractions as well as the whole cell, coupled with transcriptomics data analysis of normal compared with KD fibroblasts. We then applied novel integrative bioinformatics analysis to demonstrate that NF-kB-p65 (RELA) from the cytosolic fraction and CAPN2 from the whole-cell lysate were statistically significantly upregulated in KD and associated with alterations in relevant key signaling pathways, including apoptosis. Our findings were further confirmed by showing upregulation of both RELA and CAPN2 in KD using flow cytometry and immunohistochemistry. Moreover, functional evaluation using real-time cell analysis and flow cytometry demonstrated that both omeprazole and dexamethasone inhibited the growth of KD fibroblasts by enhancing the rate of apoptosis. In conclusion, subcellular fractionation and metaproteogenomic analyses have identified, to our knowledge, 2 previously unreported biomarkers of significant relevance to keloid diagnostics and therapeutics.
{"title":"Subcellular Fractionation and Metaproteogenomic Identification and Validation of Key Differentially Expressed Molecular Targets for Keloid Disease.","authors":"Elvis B Kidzeru, Musalula Sinkala, Temwani Chalwa, Relebohile Matobole, Madeha Alkelani, Zeinab Ghasemishahrestani, Stanley K Mbandi, Jonathan Blackburn, David L Tabb, Henry Ademola Adeola, Nonhlanhla P Khumalo, Ardeshir Bayat","doi":"10.1016/j.jid.2024.07.010","DOIUrl":"10.1016/j.jid.2024.07.010","url":null,"abstract":"<p><p>Keloid disease (KD) is a common connective tissue disorder of unknown aetiopathogenesis with ill-defined treatment. Keloid scars present as exophytic fibroproliferative reticular lesions postcutaneous injury, and even though KD remains neoplastically benign, keloid lesions behave locally aggressive, invasive and expansive. To date, there is limited understanding and validation of biomarkers identified through combined proteomic and genomic evaluation of KD. Therefore, the aim in this study was to identify putative causative candidates in KD by performing a comprehensive proteomics analysis of subcellular fractions as well as the whole cell, coupled with transcriptomics data analysis of normal compared with KD fibroblasts. We then applied novel integrative bioinformatics analysis to demonstrate that NF-kB-p65 (RELA) from the cytosolic fraction and CAPN2 from the whole-cell lysate were statistically significantly upregulated in KD and associated with alterations in relevant key signaling pathways, including apoptosis. Our findings were further confirmed by showing upregulation of both RELA and CAPN2 in KD using flow cytometry and immunohistochemistry. Moreover, functional evaluation using real-time cell analysis and flow cytometry demonstrated that both omeprazole and dexamethasone inhibited the growth of KD fibroblasts by enhancing the rate of apoptosis. In conclusion, subcellular fractionation and metaproteogenomic analyses have identified, to our knowledge, 2 previously unreported biomarkers of significant relevance to keloid diagnostics and therapeutics.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914984","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 : 2024-08-03DOI: 10.1016/j.jid.2024.07.007
Mariko Ogawa-Momohara, Thomas Vazquez, Felix Chin, Meena Sharma, Joshua Dan, Grant Sprow, Victoria P Werth
{"title":"Multiplexed Mass Cytometry of Cutaneous Lupus Erythematosus and Dermatomyositis Skin: An In-depth, B-Cell-Directed Immunoprofile.","authors":"Mariko Ogawa-Momohara, Thomas Vazquez, Felix Chin, Meena Sharma, Joshua Dan, Grant Sprow, Victoria P Werth","doi":"10.1016/j.jid.2024.07.007","DOIUrl":"10.1016/j.jid.2024.07.007","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891459","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 : 2024-07-30DOI: 10.1016/j.jid.2024.06.1277
David O Croitoru, Vincent Piguet
{"title":"Endolysins Target Bad Neighbors in the Wound Microbial Community.","authors":"David O Croitoru, Vincent Piguet","doi":"10.1016/j.jid.2024.06.1277","DOIUrl":"https://doi.org/10.1016/j.jid.2024.06.1277","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794464","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 : 2024-07-29DOI: 10.1016/j.jid.2024.04.035
Alice McDonald, Rahul Karnik, Veronica Campbell, Jeff Davis, Sara Chavoshi, Anthony Slavin, Kirti Sharma, Jared Gollob, Afsaneh Alavi
Hidradenitis suppurativa (HS) is a chronic inflammatory disease manifesting as painful dermal nodules, abscesses, and tunnels. Activation of the IL-1R/toll-like receptor pathway is strongly implicated in the pathogenesis of HS; thus, the role of a key signaling node, IRAK4, was investigated in a noninterventional study (NCT04440410) that enrolled 30 patients with HS. IRAK4 expression was evaluated in blood and lesional, perilesional, and nonlesional skin biopsies. PBMCs expressed IRAK4, with significantly higher levels in monocytes (P ≤ .0001). Ex vivo treatment of PBMCs with KT-474, a targeted degrader of IRAK4, robustly decreased IRAK4 in all immune cell types from healthy volunteers and patients with HS. Ex vivo treatment of toll-like receptor-stimulated healthy donor monocytes with KT-474 decreased IRAK4 protein levels and inhibited inflammatory cytokine production. In HS skin samples, IRAK4 protein levels were significantly higher in lesional than in nonlesional tissue (P ≤ .0001), and IRAK4-positive immune infiltrate increased with greater disease severity. Multiple inflammatory mediators were upregulated in HS lesional skin, correlating with IRAK4 overexpression. These data confirm the significance of the IL-1R/toll-like receptor pathway in the pathogenesis of HS and provide support for ongoing clinical studies evaluating KT-474 in the treatment of HS.
{"title":"IRAK4 Is Overexpressed in Hidradenitis Suppurativa Skin and Correlates with Inflammatory Biomarkers.","authors":"Alice McDonald, Rahul Karnik, Veronica Campbell, Jeff Davis, Sara Chavoshi, Anthony Slavin, Kirti Sharma, Jared Gollob, Afsaneh Alavi","doi":"10.1016/j.jid.2024.04.035","DOIUrl":"10.1016/j.jid.2024.04.035","url":null,"abstract":"<p><p>Hidradenitis suppurativa (HS) is a chronic inflammatory disease manifesting as painful dermal nodules, abscesses, and tunnels. Activation of the IL-1R/toll-like receptor pathway is strongly implicated in the pathogenesis of HS; thus, the role of a key signaling node, IRAK4, was investigated in a noninterventional study (NCT04440410) that enrolled 30 patients with HS. IRAK4 expression was evaluated in blood and lesional, perilesional, and nonlesional skin biopsies. PBMCs expressed IRAK4, with significantly higher levels in monocytes (P ≤ .0001). Ex vivo treatment of PBMCs with KT-474, a targeted degrader of IRAK4, robustly decreased IRAK4 in all immune cell types from healthy volunteers and patients with HS. Ex vivo treatment of toll-like receptor-stimulated healthy donor monocytes with KT-474 decreased IRAK4 protein levels and inhibited inflammatory cytokine production. In HS skin samples, IRAK4 protein levels were significantly higher in lesional than in nonlesional tissue (P ≤ .0001), and IRAK4-positive immune infiltrate increased with greater disease severity. Multiple inflammatory mediators were upregulated in HS lesional skin, correlating with IRAK4 overexpression. These data confirm the significance of the IL-1R/toll-like receptor pathway in the pathogenesis of HS and provide support for ongoing clinical studies evaluating KT-474 in the treatment of HS.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861997","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 : 2024-07-22DOI: 10.1016/j.jid.2024.07.004
Evon Low, Lucy A Smith, Satomi Miwa, Edward Fielder, Stefan Przyborski, Thomas von Zglinicki
{"title":"Senescent Dermal Fibroblasts Decrease Stemness in Basal Keratinocytes in a Bioengineered Model of Human Full-Thickness Skin.","authors":"Evon Low, Lucy A Smith, Satomi Miwa, Edward Fielder, Stefan Przyborski, Thomas von Zglinicki","doi":"10.1016/j.jid.2024.07.004","DOIUrl":"10.1016/j.jid.2024.07.004","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141763678","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}