JCI insightPub Date : 2025-04-15eCollection Date: 2025-05-22DOI: 10.1172/jci.insight.188658
Philip F Halloran, Jessica Chang, Martina Mackova, Katelynn S Madill-Thomsen, Enver Akalin, Tarek Alhamad, Sanjiv Anand, Miha Arnol, Rajendra Baliga, Mirosław Banasik, Christopher D Blosser, Georg Böhmig, Daniel Brennan, Jonathan Bromberg, Klemens Budde, Andrzej Chamienia, Kevin Chow, Michał Ciszek, Declan de Freitas, Dominika Dęborska-Materkowska, Alicja Debska-Ślizień, Arjang Djamali, Leszek Domański, Magdalena Durlik, Gunilla Einecke, Farsad Eskandary, Richard Fatica, Iman Francis, Justyna Fryc, John Gill, Jagbir Gill, Maciej Glyda, Sita Gourishankar, Marta Gryczman, Gaurav Gupta, Petra Hruba, Peter Hughes, Arskarapurk Jittirat, Zeljka Jurekovic, Layla Kamal, Mahmoud Kamel, Sam Kant, Nika Kojc, Joanna Konopa, James Lan, Roslyn B Mannon, Arthur Matas, Joanna Mazurkiewicz, Marius Miglinas, Thomas Mueller, Marek Myślak, Seth Narins, Beata Naumnik, Anita Patel, Agnieszka Perkowska-Ptasińska, Michael Picton, Grzegorz Piecha, Emilio Poggio, Silvie Rajnochová Bloudíčkova, Thomas Schachtner, Soroush Shojai, Majid Ln Sikosana, Janka Slatinská, Katarzyna Smykal-Jankowiak, Ashish Solanki, Željka Veceric Haler, Ondrej Viklicky, Ksenija Vucur, Matthew R Weir, Andrzej Wiecek, Zbigniew Włodarczyk, Harold Yang, Ziad Zaky, Patrick T Gauthier, Christian Hinze
{"title":"A cross-sectional study of the role of epithelial cell injury in kidney transplant outcomes.","authors":"Philip F Halloran, Jessica Chang, Martina Mackova, Katelynn S Madill-Thomsen, Enver Akalin, Tarek Alhamad, Sanjiv Anand, Miha Arnol, Rajendra Baliga, Mirosław Banasik, Christopher D Blosser, Georg Böhmig, Daniel Brennan, Jonathan Bromberg, Klemens Budde, Andrzej Chamienia, Kevin Chow, Michał Ciszek, Declan de Freitas, Dominika Dęborska-Materkowska, Alicja Debska-Ślizień, Arjang Djamali, Leszek Domański, Magdalena Durlik, Gunilla Einecke, Farsad Eskandary, Richard Fatica, Iman Francis, Justyna Fryc, John Gill, Jagbir Gill, Maciej Glyda, Sita Gourishankar, Marta Gryczman, Gaurav Gupta, Petra Hruba, Peter Hughes, Arskarapurk Jittirat, Zeljka Jurekovic, Layla Kamal, Mahmoud Kamel, Sam Kant, Nika Kojc, Joanna Konopa, James Lan, Roslyn B Mannon, Arthur Matas, Joanna Mazurkiewicz, Marius Miglinas, Thomas Mueller, Marek Myślak, Seth Narins, Beata Naumnik, Anita Patel, Agnieszka Perkowska-Ptasińska, Michael Picton, Grzegorz Piecha, Emilio Poggio, Silvie Rajnochová Bloudíčkova, Thomas Schachtner, Soroush Shojai, Majid Ln Sikosana, Janka Slatinská, Katarzyna Smykal-Jankowiak, Ashish Solanki, Željka Veceric Haler, Ondrej Viklicky, Ksenija Vucur, Matthew R Weir, Andrzej Wiecek, Zbigniew Włodarczyk, Harold Yang, Ziad Zaky, Patrick T Gauthier, Christian Hinze","doi":"10.1172/jci.insight.188658","DOIUrl":"10.1172/jci.insight.188658","url":null,"abstract":"<p><strong>Background: </strong>Expression of acute kidney injury-associated (AKI-associated) transcripts in kidney transplants may reflect recent injury and accumulation of epithelial cells in \"failed repair\" states. We hypothesized that the phenomenon of failed repair could be associated with deterioration and failure in kidney transplants.</p><p><strong>Methods: </strong>We defined injury-induced transcriptome states in 4,502 kidney transplant biopsies injury-induced gene sets and classifiers previously developed in transplants.</p><p><strong>Results: </strong>In principal component analysis (PCA), PC1 correlated with both acute and chronic kidney injury and related inflammation and PC2 with time posttransplant. Positive PC3 was a dimension that correlated with epithelial remodeling pathways and anticorrelated with inflammation. Both PC1 and PC3 correlated with reduced survival, with PC1 effects strongly increasing over time whereas PC3 effects were independent of time. In this model, we studied the expression of 12 \"new\" gene sets annotated in single-nucleus RNA-sequencing studies of epithelial cells with failed repair in native kidneys. The new gene sets reflecting epithelial-mesenchymal transition correlated with injury PC1 and PC3, lower estimated glomerular filtration rate, higher donor age, and future failure as strongly as any gene sets previously derived in transplants and were independent of nephron segment of origin and graft rejection.</p><p><strong>Conclusion: </strong>These results suggest 2 dimensions in the kidney transplant response to injury: PC1, AKI-induced changes, failed repair, and inflammation; and PC3, a response involving epithelial remodeling without inflammation. Increasing kidney age amplifies PC1 and PC3.</p><p><strong>Trial registration: </strong>INTERCOMEX (ClinicalTrials.gov NCT01299168); Trifecta-Kidney (ClinicalTrials.gov NCT04239703).</p><p><strong>Funding: </strong>Genome Canada; Natera, Inc.; and Thermo Fisher Scientific.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-04-15eCollection Date: 2025-05-22DOI: 10.1172/jci.insight.189151
Ganlin Qu, Henrique Al Ribeiro, Angelica L Solomon, Luis Sordo Vieira, Yana Goddard, Nickolas G Diodati, Arantxa V Lazarte, Matthew Wheeler, Reinhard Laubenbacher, Borna Mehrad
{"title":"The heme scavenger hemopexin protects against lung injury during aspergillosis by mitigating release of neutrophil extracellular traps.","authors":"Ganlin Qu, Henrique Al Ribeiro, Angelica L Solomon, Luis Sordo Vieira, Yana Goddard, Nickolas G Diodati, Arantxa V Lazarte, Matthew Wheeler, Reinhard Laubenbacher, Borna Mehrad","doi":"10.1172/jci.insight.189151","DOIUrl":"10.1172/jci.insight.189151","url":null,"abstract":"<p><p>Invasive aspergillosis is characterized by lung hemorrhage and release of extracellular heme, which promotes fungal growth. Heme can also mediate tissue injury directly, and both fungal growth and lung injury may induce hemorrhage. To assimilate these interdependent processes, we hypothesized that, during aspergillosis, heme mediates direct lung injury independent of fungal growth, leading to worse infection outcomes, and the scavenger protein hemopexin mitigates these effects. Mice with neutropenic aspergillosis developed a time-dependent increase in lung extracellular heme and a corresponding hemopexin induction. Hemopexin deficiency resulted in markedly increased lung injury, fungal growth, and lung hemorrhage. Using a computational model of the interactions of Aspergillus, heme, and the host, we predicted a critical role for heme-mediated generation of neutrophil extracellular traps (NETs) in this infection. We tested this prediction using a fungal strain unable to grow at body temperature and found that extracellular heme and fungal exposure synergized to induce lung injury by promoting NET release, and disruption of NET was sufficient to attenuate lung injury and fungal burden. These data implicate heme-mediated NETosis in both lung injury and fungal growth during aspergillosis, resulting in a detrimental positive feedback cycle that can be interrupted by scavenging heme or disrupting NETs.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144025512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-04-15eCollection Date: 2025-05-22DOI: 10.1172/jci.insight.181778
Adrian Zietara, Lashodya V Dissanayake, Melissa Lowe, Biyang Xu, Vladislav Levchenko, Vasundhara Kain, Ganesh V Halade, Christine A Klemens, Oleg Palygin, Alexander Staruschenko
{"title":"Potassium supplementation and depletion during development of salt-sensitive hypertension in male and female SS rats.","authors":"Adrian Zietara, Lashodya V Dissanayake, Melissa Lowe, Biyang Xu, Vladislav Levchenko, Vasundhara Kain, Ganesh V Halade, Christine A Klemens, Oleg Palygin, Alexander Staruschenko","doi":"10.1172/jci.insight.181778","DOIUrl":"10.1172/jci.insight.181778","url":null,"abstract":"<p><p>The dietary sodium/potassium ratio is positively correlated with blood pressure, and understanding this relationship is crucial for improving hypertension treatment. Moreover, few studies have examined these effects in both sexes. In this study, we aimed to investigate how supplementing (1.41% K+; HK) or depleting (DK) dietary potassium affects the development of salt-sensitive (SS) hypertension in male and female Dahl SS rats. Potassium supplementation attenuated blood pressure during 5 weeks of high-salt (4% NaCl) diet in male but not in female rats. In contrast, a potassium-deficient diet prevented the development of salt-induced hypertension in both sexes, though this effect is unlikely to be protective. Both males and females on the DK diet were hypokalemic and had diminished heart rates and reduced weight gain; furthermore, females experienced high mortality. RNA-Seq of kidney cortical tissue revealed a number of genes that may underlie the sex-specific differences in phenotype. Male rats supplemented with potassium exhibited a decreased number and size of WNK4 puncta, whereas in potassium-supplemented females, there was no difference in puncta count and there was an increase in puncta size. Our data indicate there are sex-dependent differences in response to dietary potassium in hypertension and that the distal nephron compensates for severe potassium deficiency.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-04-15eCollection Date: 2025-05-22DOI: 10.1172/jci.insight.189901
Liliya Tyutyunyk-Massey, Zibo Chen, Xiuxia Liu, Masanori Kawakami, Adam Harned, Yeap Ng, Brian Luke, Samuel C Okpechi, Blessing Ogunlade, Yair Alfaro, Roberto Weigert, Kedar Narayan, Xi Liu, Ethan Dmitrovsky
{"title":"CDK2 inhibition produces a persistent population of polyploid cancer cells.","authors":"Liliya Tyutyunyk-Massey, Zibo Chen, Xiuxia Liu, Masanori Kawakami, Adam Harned, Yeap Ng, Brian Luke, Samuel C Okpechi, Blessing Ogunlade, Yair Alfaro, Roberto Weigert, Kedar Narayan, Xi Liu, Ethan Dmitrovsky","doi":"10.1172/jci.insight.189901","DOIUrl":"10.1172/jci.insight.189901","url":null,"abstract":"<p><p>Aneuploidy, a cancer hallmark, drives chromosomal instability, drug resistance, and clinically aggressive tumors. Cyclin-dependent kinase 2 (CDK2) antagonism with independent inhibitors or CDK2 knockdown triggered anaphase catastrophe. This disrupts supernumerary centrosome clustering, causing multipolar division and apoptosis. Time-lapse fluorescence microscopy of fluorescent ubiquitination-based cell cycle indicator (FUCCI) cell cycle probes transduced into aneuploid lung cancer cells revealed distinct fates of bipolar and polyploid cells after CDK2 inhibition. Apoptosis occurred in multipolar progeny but was repressed in persistent polyploid cancer cells. RNA-Seq analyses after CDK2 inhibition of 4N versus 2N lung cancer cells were enriched for CDK1 pathway and KIF family members. The Cancer Genome Atlas (TCGA) analysis of lung cancers indicated that CDK1 and KIF family member overexpression was associated with an unfavorable survival. Intravital microscopy of transplanted lung cancer cells in mice extended findings from the in vitro to in vivo settings. CDK2 inhibition of tumor-bearing mice produced polyploid cancer cells in vivo. These cancer cells were resistant to apoptosis and proliferated despite CDK2 inhibition. In contrast, polyploid populations were rarely detected in CDK2-inhibited human alveolar epithelial cells. These findings are translationally relevant. Combined targeting of CDK2 with CDK1 or kinesin family member antagonists should eliminate polyploid cancer cells, promote apoptosis, and augment antineoplastic effects.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-04-10eCollection Date: 2025-05-22DOI: 10.1172/jci.insight.189330
Jyotsana Pandey, Jennifer L Larson-Casey, Mallikarjun H Patil, Chao He, Nisarat Pinthong, A Brent Carter
{"title":"The PERK/ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis.","authors":"Jyotsana Pandey, Jennifer L Larson-Casey, Mallikarjun H Patil, Chao He, Nisarat Pinthong, A Brent Carter","doi":"10.1172/jci.insight.189330","DOIUrl":"10.1172/jci.insight.189330","url":null,"abstract":"<p><p>Asbestosis is a prototypical type of fibrosis that is progressive and does not resolve. ER stress is increased in multiple cell types that contribute to fibrosis; however, the mechanism(s) by which ER stress in lung macrophages contributes to fibrosis is poorly understood. Here, we show that ER stress resulted in protein kinase RNA-like ER kinase (PERK; Eif2ak3) activation in humans with asbestosis. Similar results were seen in asbestos-injured mice. Mice harboring a conditional deletion of Eif2ak3 were protected from fibrosis. Lung macrophages from asbestosis individuals had evidence of metabolic reprogramming to fatty acid oxidation (FAO). Eif2ak3fl/fl mice had increased oxygen consumption rate (OCR), whereas OCR in Eif2ak3-/- Lyz2-cre mice was reduced to control levels. PERK increased activating transcription factor 4 (Atf4) expression, and ATF4 bound to the Ppargc1a promoter to increase its expression. GSK2656157, a PERK-specific inhibitor, reduced FAO, Ppargc1a, and Aft4 in lung macrophages and reversed established fibrosis in mice. These observations suggest that PERK is a therapeutic target to reverse established fibrosis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-04-08DOI: 10.1172/jci.insight.186259
Anna B Morris, Max W Adelman, Kelsey B Bennion, Catherine D Martinez, Kem-Maria McCook, Michael H Woodworth, Charles R Langelier, Nadine Rouphael, Christopher D Scharer, Cheryl L Maier, Colleen S Kraft, Mandy L Ford
{"title":"Fgl2 regulates FcγRIIB+CD8+ T cell responses during infection.","authors":"Anna B Morris, Max W Adelman, Kelsey B Bennion, Catherine D Martinez, Kem-Maria McCook, Michael H Woodworth, Charles R Langelier, Nadine Rouphael, Christopher D Scharer, Cheryl L Maier, Colleen S Kraft, Mandy L Ford","doi":"10.1172/jci.insight.186259","DOIUrl":"10.1172/jci.insight.186259","url":null,"abstract":"<p><p>While the inhibitory receptor FcγRIIB has been shown to be upregulated on activated CD8+ T cells in both mice and humans, its effect on T cell fate during infection has not been fully elucidated. We identified an increase in FcγRIIB-expressing CD8+ T cells in patients with COVID-19 relative to healthy controls as well as in mouse models of viral infection. Despite its well-known role as an Fc receptor, FcγRIIB also ligates the immunosuppressive cytokine Fgl2, resulting in CD8+ T cell apoptosis. Both chronic LCMV infection in mice and COVID-19 in humans resulted in a significant increase in plasma Fgl2. Transfer of CD8+ T cells into a Fgl2-replete, but not Fgl2-devoid, environment resulted in elimination of FcγRIIB+, but not FcγRIIB-, CD8+ T cells. Similarly, plasma Fgl2 was directly proportional to CD8+ T cell lymphopenia in patients with COVID-19. RNA-Seq analysis demonstrated that Fgl2 was produced by murine virus-specific CD8+ T cells, with an increase in Fgl2 in CD8+ T cells elicited during chronic versus acute viral infection. Fgl2 was also upregulated in CD8+ T cells from patients with COVID-19 versus healthy controls. In summary, CD8+ T cell production of Fgl2 during viral infection underpinned an FcγRIIB-mediated loss of CD8+ T cell immunity in both mice and humans.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-04-08eCollection Date: 2025-05-08DOI: 10.1172/jci.insight.178689
Inwon Park, Seonghye Kim, Young Woo Um, Hee Eun Kim, Jae Hyuk Lee, Sejoong Kim, Pilhan Kim, You Hwan Jo
{"title":"Intravital imaging of peritubular microcirculation impairment in cisplatin-induced acute kidney injury.","authors":"Inwon Park, Seonghye Kim, Young Woo Um, Hee Eun Kim, Jae Hyuk Lee, Sejoong Kim, Pilhan Kim, You Hwan Jo","doi":"10.1172/jci.insight.178689","DOIUrl":"10.1172/jci.insight.178689","url":null,"abstract":"<p><p>Despite the accumulation of cisplatin in proximal tubules, direct visualization of the surrounding peritubular microcirculation, including its change in cisplatin-induced acute kidney injury (AKI), is lacking. Here, using fluorescence and cellular angiography through video-rate high-resolution intravital microscopy, progressive disturbance of peritubular microcirculation in cisplatin-induced AKI in mice was demonstrated. Fluorescence angiography revealed increasing perfusion defects, with a stepwise rise in time to peak (TTP), originating from capillaries surrounding S1 segments. Cellular angiography demonstrated a progressive decrease in the velocity and track length of individual erythrocytes during AKI progression, accompanied by a sequential decrease in the functional capillary ratio (FCR). Changes in the perfusion area, TTP, and FCR preceded significant changes in blood urea nitrogen and cystatin C, suggesting the potential for early diagnosis. Although neutrophil infiltration near proximal tubules increased throughout the progression, it did not cause obstruction of the peritubular microcirculation. Depletion of neutrophils increased mortality due to systemic side effects, whereas functional inactivation of neutrophils using an anti-CD11b antibody improved peritubular microcirculation in cisplatin-induced AKI. This approach enables direct visualization and quantification of peritubular microcirculation and immune cell dynamics, providing insights into renal pathophysiology and potential therapeutic strategies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-04-08DOI: 10.1172/jci.insight.192689
Kyu Y Rhee, Charles W Emala, Emily Jane Gallagher, Don C Rockey, Patrick J Hu, Jatin M Vyas, Daniel P Cook, Tiffany C Scharschmidt, Olujimi A Ajijola, Christopher S Williams
{"title":"Paving the physician-scientist career path: from grassroots gathering to national forum.","authors":"Kyu Y Rhee, Charles W Emala, Emily Jane Gallagher, Don C Rockey, Patrick J Hu, Jatin M Vyas, Daniel P Cook, Tiffany C Scharschmidt, Olujimi A Ajijola, Christopher S Williams","doi":"10.1172/jci.insight.192689","DOIUrl":"10.1172/jci.insight.192689","url":null,"abstract":"<p><p>The Alliance for Academic Internal Medicine (AAIM) first convened a workshop in 2015 that brought a small group of internal medicine program directors together who recognized the growing success of early-phase physician-scientist training programs but the unclear path afterward for these trainees. The meeting subsequently evolved into what is now the annual American Society for Clinical Investigation/AAIM/Burroughs Wellcome Fund (ASCI/AAIM/BWF) Physician-Scientist Pathways Workshop, which continues to bring stakeholders together to discuss the obstacles to success that physician-scientists face at all stages of their careers. This perspective presents the history and goals of the workshop, with an emphasis on the most recent meeting in 2024, and looks ahead to the work that still needs to be done to ensure a robust physician-scientist workforce.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-04-08DOI: 10.1172/jci.insight.184072
Tianfu Wang, Runping Duan, Zhaohuai Li, Bowen Zhang, Qi Jiang, Loujing Jiang, Jianjie Lv, Wenru Su, Lei Feng
{"title":"Lipid metabolism analysis reveals that DGAT1 regulates Th17 survival by controlling lipid peroxidation in uveitis.","authors":"Tianfu Wang, Runping Duan, Zhaohuai Li, Bowen Zhang, Qi Jiang, Loujing Jiang, Jianjie Lv, Wenru Su, Lei Feng","doi":"10.1172/jci.insight.184072","DOIUrl":"10.1172/jci.insight.184072","url":null,"abstract":"<p><p>Lipid metabolism is closely linked with antitumor immunity and autoimmune disorders. However, the precise role of lipid metabolism in uveitis pathogenesis is not clear. In our study, we analyzed the single-cell RNA-Seq (scRNA-Seq) data from cervical draining lymph nodes (CDLNs) of mice with experimental autoimmune uveitis (EAU), revealing an increased abundance of fatty acids in Th17 cells. Subsequent scRNA-Seq analysis identified the upregulation of DGAT1 expression in EAU and its marked reduction under various immunosuppressive agents. Suppression of DGAT1 prevented the conversion of fatty acids into neutral lipid droplets, resulting in the accumulation of lipid peroxidation and subsequent reduction in the proportion of Th17 cells. Inhibiting lipid peroxidation by Ferrostatin-1 effectively restored Th17 cell numbers that were decreased by DGAT1 inhibitor. Moreover, we validated the upregulation of DGAT1 in CD4+ T cells from patients with Vogt-Koyanagi-Harada (VKH) disease, a human uveitis. Inhibiting DGAT1 induced lipid peroxidation in human CD4+ T cells and reduced the proportion of Th17 cells. Collectively, our study focused on elucidating the regulatory mechanisms underlying Th17 cell survival and proposed that targeting DGAT1 may hold promise as a therapeutic approach for uveitis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-04-08DOI: 10.1172/jci.insight.180309
Susanne Rueger, Eva Gruener, Danni Wang, Faiaz Shaik Abdool, Veronica Ober, Theresa Vallée, Renate Stirner, Raffaele Conca, Immanuel Andrä, Lisa Rogers, Robert Zahn, Elke Gersbacher, Joanna Eger, Ramona Pauli, Nils Postel, Christoph D Spinner, Jörg J Vehreschild, Melanie Stecher, Hans Nitschko, Josef Eberle, Johannes R Bogner, Ulrich Seybold, Rika Draenert, Al Leslie, Henrik N Kløverpris, Christof Geldmacher, Maximilian Muenchhoff, Kathrin Held, Julia Roider
{"title":"Early treatment and PD1 inhibition enhance HIV-specific functionality of follicular CD8+ T cells.","authors":"Susanne Rueger, Eva Gruener, Danni Wang, Faiaz Shaik Abdool, Veronica Ober, Theresa Vallée, Renate Stirner, Raffaele Conca, Immanuel Andrä, Lisa Rogers, Robert Zahn, Elke Gersbacher, Joanna Eger, Ramona Pauli, Nils Postel, Christoph D Spinner, Jörg J Vehreschild, Melanie Stecher, Hans Nitschko, Josef Eberle, Johannes R Bogner, Ulrich Seybold, Rika Draenert, Al Leslie, Henrik N Kløverpris, Christof Geldmacher, Maximilian Muenchhoff, Kathrin Held, Julia Roider","doi":"10.1172/jci.insight.180309","DOIUrl":"10.1172/jci.insight.180309","url":null,"abstract":"<p><p>People living with HIV treated during acute infection are the group for whom achieving functional cure appears most viable. Follicular CD8+ T cells could contribute to HIV reservoir clearance by accessing B cell follicles through CXCR5 expression. This study examines peripheral follicular CD8+ T cells using flow cytometry, transcriptome analyses, and functional assays in people treated during acute (n = 37) and chronic (n = 18) infection, as well as in individuals naturally controlling HIV (n = 20) and living without HIV (n = 10). Our results reveal that early, as opposed to late, treatment initiation preserves antiviral effector functions of follicular CD8+ T cells, which are further enhanced by PD1 inhibition. We also identify a correlation between follicular CD8+ T cells and intact proviral HIV DNA levels in acute, but not chronic, infection. Longitudinal transcriptomic analysis of peripheral effector cells after 48 weeks of suppressive therapy indicated traits of recent antigen exposure, suggesting potential recirculation into lymphoid tissue. These findings underscore the pivotal role of follicular CD8+ T cells in anti-HIV responses and support investigating targeted cure strategies, such as anti-PD1 therapy, especially in individuals initiating treatment during acute infection.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}