JCI insightPub Date : 2025-06-10DOI: 10.1172/jci.insight.184240
Ethan M Grund, Benjamin Ds Clarkson, Susanna Pucci, Maria S Westphal, Carolina Muniz Partida, Sara A Muhammad, Charles L Howe
{"title":"Pentose phosphate pathway inhibition metabolically reprograms CD8+ T cells and disrupts CNS autoimmunity.","authors":"Ethan M Grund, Benjamin Ds Clarkson, Susanna Pucci, Maria S Westphal, Carolina Muniz Partida, Sara A Muhammad, Charles L Howe","doi":"10.1172/jci.insight.184240","DOIUrl":"https://doi.org/10.1172/jci.insight.184240","url":null,"abstract":"<p><p>Multiple sclerosis is characterized by CNS infiltration of auto-reactive immune cells that drive both acute inflammatory demyelination and chronic progressive axonal and neuronal injury. Expanding evidence implicates CD8+ anti-neural T cells in the irreversible neurodegeneration that underlies progression in multiple sclerosis, yet therapies specifically targeting this cell population are limited. CD8+ T cells from patients with MS exhibit increased engagement of the pentose phosphate pathway. Pharmacologic inhibition of the pentose phosphate pathway reduced glycolysis, glucose uptake, NADPH production, ATP production, proliferation, and proinflammatory cytokine secretion in CD8+ T cells activated by ligation of CD3 and CD28. Pentose phosphate pathway inhibition also prevented CD8+ T cell-mediated antigen-specific neuronal injury in vitro and in both an adoptive transfer-based cuprizone model of demyelination and in mice with experimental autoimmune encephalomyelitis. Notably, transcriptional profiling of CNS-infiltrating CD8+ T cells in patients with MS indicated increased pentose phosphate pathway engagement, suggesting that this pathway is involved in CD8+ T cell-mediated injury of axons and neurons in the demyelinated CNS. Inhibiting the pentose phosphate pathway disrupts CD8+ T cell metabolic reprogramming and effector functions, suggesting that such inhibition may serve as a therapeutic strategy to prevent neurodegeneration in patients with progressive MS.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-10DOI: 10.1172/jci.insight.193826
Leena B Mithal, Mark E Becker, Ted Ling-Hu, Young Ah Goo, Sebastian Otero, Aspen Kremer, Surya Pandey, Nicola Lancki, Yawei Li, Yuan Luo, William Grobman, Denise Scholtens, Karen K Mestan, Patrick C Seed, Judd F Hultquist
{"title":"Cord blood proteomics identifies biomarkers of early-onset neonatal sepsis.","authors":"Leena B Mithal, Mark E Becker, Ted Ling-Hu, Young Ah Goo, Sebastian Otero, Aspen Kremer, Surya Pandey, Nicola Lancki, Yawei Li, Yuan Luo, William Grobman, Denise Scholtens, Karen K Mestan, Patrick C Seed, Judd F Hultquist","doi":"10.1172/jci.insight.193826","DOIUrl":"https://doi.org/10.1172/jci.insight.193826","url":null,"abstract":"<p><strong>Background: </strong>Symptoms of early-onset sepsis (EOS) in preterm infants are nonspecific, overlapping with normal postnatal physiological adaptations and noninfectious pathologies. This clinical uncertainty and the lack of reliable EOS diagnostics results in liberal use of antibiotics in the first days to weeks of life, leading to increased risk of antibiotic-related morbidities in infants who do not have an invasive infection.</p><p><strong>Methods: </strong>To identify potential biomarkers for EOS in newborn infants, we used unlabelled tandem mass spectrometry proteomics to identify differentially abundant proteins in the umbilical cord blood of infants with and without culture-confirmed EOS. Proteins were then confirmed using immunoassay, and logistic regression and random forest models were built including both biomarker concentration and clinical variables to predict EOS.</p><p><strong>Results: </strong>These data identified five proteins that were significantly upregulated in infants with EOS, three of which (serum amyloid A, C-reactive protein, and lipopolysaccharide-binding protein) were confirmed using a quantitative immunoassay. The random forest classifier for EOS was applied to a cohort of infants with culture-negative presumed sepsis (PS). Most PS infants were classified as resembling control infants, having low EOS biomarker concentrations.</p><p><strong>Conclusion: </strong>These results suggest that cord blood biomarker screening may be useful for early stratification of EOS risk among neonates, improving targeted, evidence-based use of antibiotics early in life.</p><p><strong>Funding: </strong>National Institutes of Health, Gerber Foundation, Friends of Prentice, Thrasher Research Fund, Ann & Robert H. Lurie Children's Hospital, Stanley Manne Children's Research Institute of Lurie Children's.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-10DOI: 10.1172/jci.insight.189503
Yang Zhang, Xuyang Yang, Su Zhang, Qing Huang, Sicheng Liu, Lei Qiu, Mingtian Wei, Xiangbing Deng, Wenjian Meng, Hai-Ning Chen, Yaguang Zhang, Junhong Han, Ziqiang Wang
{"title":"MicroRNA-6084 orchestrates angiogenesis and liver metastasis in colorectal cancer via extracellular vesicles.","authors":"Yang Zhang, Xuyang Yang, Su Zhang, Qing Huang, Sicheng Liu, Lei Qiu, Mingtian Wei, Xiangbing Deng, Wenjian Meng, Hai-Ning Chen, Yaguang Zhang, Junhong Han, Ziqiang Wang","doi":"10.1172/jci.insight.189503","DOIUrl":"https://doi.org/10.1172/jci.insight.189503","url":null,"abstract":"<p><p>The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are still not fully understood. Hypoxia-induced extracellular vesicles (H-EVs) derived from tumors have emerged as key players in inducing angiogenesis by transferring non-coding RNAs. However, the specific role of CRC-derived hypoxic EVs (H-EVs) in regulating the formation of the pre-metastatic microenvironment (PMN) by inducing angiogenesis remains unclear. Our study demonstrates that H-EVs induce both angiogenesis and liver metastasis. Through microRNA microarray analysis, we identified a reduction in miR-6084 levels within H-EVs. We found that miR-6084 inhibits angiogenesis by being transferred to endothelial cells via EVs. In endothelial cells, miR-6084 directly targets ANGPTL4 mRNA, thereby suppressing angiogenesis through ANGPTL4-mediated JAK2/STAT3 pathway. Furthermore, we uncovered that SP1 acts as a transcription factor regulating miR-6084 transcription, while HIF1A decreases miR-6084 expression by promoting SP1 protein dephosphorylation and facilitating ubiquitin‒proteasome degradation in SW620 cells. In clinical samples, we observed low expression of miR-6084 in plasma-derived EVs from CRC patients with liver metastasis. In summary, our findings suggest that CRC-derived hypoxic EVs promote angiogenesis and liver metastasis through the HIF1A/SP1/miR-6084/ANGPTL4 axis. Additionally, miR-6084 holds promise as a potential diagnostic and prognostic biomarker for CRC liver metastasis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-10DOI: 10.1172/jci.insight.188323
Wida Amini, Lena Schemmelmann, Jan-Niklas Heming, Marina Oguama, Katharina Thomas, Helena Block, Pia Lindental, Bernadette Bardel, Andreas Margraf, Oliver Soehnlein, Anika Cappenberg, Alexander Zarbock
{"title":"Csk-mediated Src family kinase regulation dampens neutrophil infiltration during pulmonary infection.","authors":"Wida Amini, Lena Schemmelmann, Jan-Niklas Heming, Marina Oguama, Katharina Thomas, Helena Block, Pia Lindental, Bernadette Bardel, Andreas Margraf, Oliver Soehnlein, Anika Cappenberg, Alexander Zarbock","doi":"10.1172/jci.insight.188323","DOIUrl":"https://doi.org/10.1172/jci.insight.188323","url":null,"abstract":"<p><p>Neutrophil recruitment is crucial for pathogen elimination. However, precise control of the inflammatory response prevents overshooting reactions. Neutrophil activation initiates signaling resulting in integrin beta 2 (Itgb2) activation and neutrophil arrest. Src family kinases are involved in multiple cellular processes and are negatively regulated by the C-terminal Src kinase (Csk). During this study, we investigated the mechanism by which Csk regulates integrin activation and neutrophil recruitment. Here, we demonstrated that Csk deficiency in murine neutrophils resulted in increased neutrophil adhesion to the endothelium along with decreased neutrophil transmigration into inflamed tissues compared to their littermate controls. In bacterial pneumonia, infected Csk-deficient mice showed higher bacterial burdens and decreased neutrophil recruitment, while other immune cell counts and cytokine levels were not significantly different compared to control. Analyses of Csk-deficient neutrophils revealed an increased Itgb2 affinity, leading to reduced migration and intravascular crawling. Mechanistically, elevated cAMP-levels increased protein kinase A activity, which subsequently enhanced Csk activation. Csk, in turn, suppressed Src family kinases activation through phosphorylation (Y529). Hence, Csk-mediated regulation of neutrophil infiltration contributes to maintain a balanced immune response during bacterial pneumonia.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-10DOI: 10.1172/jci.insight.187799
Luis F Flores, David L Marks, Renzo E Vera, Ashley N Sigafoos, Ezequiel J Tolosa, Luciana L Almada, David R Pease, Merih D Toruner, Brian Chang, Brooke R Tader, Kayla C LaRue-Nolan, Ryan M Carr, Rondell P Graham, Catherine E Hagen, Matthew R Brown, Aleksey V Matveyenko, Katherine L Wilson, David W Dawson, Christopher L Pin, Kyle J Roux, Martin E Fernandez-Zapico
{"title":"Emerin is an effector of oncogenic KRAS-driven nuclear dynamics in pancreatic cancer.","authors":"Luis F Flores, David L Marks, Renzo E Vera, Ashley N Sigafoos, Ezequiel J Tolosa, Luciana L Almada, David R Pease, Merih D Toruner, Brian Chang, Brooke R Tader, Kayla C LaRue-Nolan, Ryan M Carr, Rondell P Graham, Catherine E Hagen, Matthew R Brown, Aleksey V Matveyenko, Katherine L Wilson, David W Dawson, Christopher L Pin, Kyle J Roux, Martin E Fernandez-Zapico","doi":"10.1172/jci.insight.187799","DOIUrl":"https://doi.org/10.1172/jci.insight.187799","url":null,"abstract":"<p><p>For over a century, scientists reported the disruption of normal nuclear shape and size in cancer. These changes have long been used as tools for diagnosis and staging of malignancies. However, to date, the mechanisms underlying these aberrant nuclear phenotypes and their biological significance remain poorly understood. Using a model of pancreatic ductal adenocarcinoma (PDAC), the major histological subtypes of pancreatic cancer, we found oncogenic mutant KRAS reduces nuclear size. Transcriptomic and protein expression analysis of mutant KRAS-expressing PDAC cells revealed differential levels of several nuclear envelope-associated genes. Further analysis demonstrated the nuclear lamina protein, Emerin (EMD), acted downstream of KRAS to mediate nuclear size reduction in PDAC. Analysis of human PDAC samples showed that increased EMD expression associates with reduced nuclear size. Finally, in vivo genetic depletion of EMD in a mutant KRAS-driven PDAC model resulted in an increased nuclear size and a reduced incidence of poorly differentiated PDAC. Thus, our data provides evidence of a novel mechanism underlying nuclear size regulation and its impact in PDAC carcinogenesis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-09DOI: 10.1172/jci.insight.184742
Jennifer K Lee, Yue He, Shireen Rl Flores, Regina R Woloshun, Xiaoyu Wang, Jacob S Shine, Pearl O Ebea-Ugwuanyi, Sitara Sriram, Melissa Fraga, Sean Zhu, Yang Yu, Iqbal Hamza, James F Collins
{"title":"Development of rat and mouse models of heme-iron absorption.","authors":"Jennifer K Lee, Yue He, Shireen Rl Flores, Regina R Woloshun, Xiaoyu Wang, Jacob S Shine, Pearl O Ebea-Ugwuanyi, Sitara Sriram, Melissa Fraga, Sean Zhu, Yang Yu, Iqbal Hamza, James F Collins","doi":"10.1172/jci.insight.184742","DOIUrl":"https://doi.org/10.1172/jci.insight.184742","url":null,"abstract":"<p><p>Heme iron (HI), derived principally from hemoglobin (Hb) in animal foods, is a highly bioavailable source of dietary iron for humans. Despite several decades of focused research, however, molecular mechanisms governing HI absorption remain undefined. Previous studies in mice and rats have not produced a consensus, definitive model of efficient HI absorption/utilization. We hypothesized that a nutritional approach, using semipurified, HI-containing diets, could be utilized to establish a tractable rodent model of HI absorption that could ultimately be employed to test the roles of receptors, transporters, and enzymes using genetic engineering technology. Experiments were designed to assess HI utilization by feeding animals AIN-93G-based, HI-enriched experimental diets formulated with lyophilized porcine RBCs, containing approximately 85% HI and 15% nonheme iron (NHI). Total iron was within the physiological range (50-75 ppm) and precisely matched NHI control diets containing ferrous sulfate were utilized as comparators. Notably, in Sprague-Dawley (S-D) rats and C57BL/6 (B6) mice, dietary HI effectively (a) resolved iron-deficiency anemia; (b) supported normal pregnancy, lactation, and neonatal development; and (c) contributed to iron loading in Hamp-KO mice and rats (modeling hereditary hemochromatosis). A nutritional paradigm has thus been established that facilitates investigation into mechanisms of HI absorption by S-D rats and B6 mice.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 11","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-09DOI: 10.1172/jci.insight.184968
Lu Ji, Leighton Pu, Jinglong Wang, Hongbin Cao, Stavros Melemenidis, Subarna Sinha, Li Guan, Eyiwunmi E Laseinde, Rie von Eyben, Sara A Richter, Jin-Min Nam, Christina Kong, Kerriann M Casey, Edward E Graves, Richard L Frock, Quynh Thu Le, Erinn B Rankin
{"title":"FTO inhibition enhances the therapeutic index of radiation therapy in head and neck cancer.","authors":"Lu Ji, Leighton Pu, Jinglong Wang, Hongbin Cao, Stavros Melemenidis, Subarna Sinha, Li Guan, Eyiwunmi E Laseinde, Rie von Eyben, Sara A Richter, Jin-Min Nam, Christina Kong, Kerriann M Casey, Edward E Graves, Richard L Frock, Quynh Thu Le, Erinn B Rankin","doi":"10.1172/jci.insight.184968","DOIUrl":"https://doi.org/10.1172/jci.insight.184968","url":null,"abstract":"<p><p>Despite aggressive chemoradiation treatment, the overall survival rate for patients with HPV- head and neck squamous cell carcinoma (HNSCC) remains poor, highlighting the urgent need for more effective drug-radiotherapy combinations to improve the therapeutic index of radiation therapy (RT). The fat mass and obesity-related gene (FTO) is emerging as a promising cancer therapeutic target; however, its role in the RT response has been underexplored. In our study, we found that both genetic and pharmacologic inhibition of FTO enhanced the efficacy of RT in human and mouse HNSCC tumor xenografts. Mechanistically, inhibition of FTO improved the RT response in HPV- HNSCC cells, which was associated with increased DNA damage, reduced efficiency of homology directed repair, and decreased formation of RAD51 homolog 1 (RAD51) foci. Importantly, pharmacologic inhibition of FTO did not exacerbate radiation-induced oral mucositis, a significant normal-tissue toxicity associated with HNSCC RT. In summary, our results indicate a role for FTO in regulating homologous recombination while identifying FTO as a potential therapeutic target to enhance the therapeutic index of RT in HPV- HNSCC treatment.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 11","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-09DOI: 10.1172/jci.insight.188325
Mazharul Maishan, Hiroki Taenaka, Bruno Evrard, Shotaro Matsumoto, Angelika Ringor, Carolyn Leroux, Rudolf Lucas, Michael A Matthay
{"title":"The lectin-like domain of TNF reduces pneumonia-induced injury in the perfused human lung.","authors":"Mazharul Maishan, Hiroki Taenaka, Bruno Evrard, Shotaro Matsumoto, Angelika Ringor, Carolyn Leroux, Rudolf Lucas, Michael A Matthay","doi":"10.1172/jci.insight.188325","DOIUrl":"https://doi.org/10.1172/jci.insight.188325","url":null,"abstract":"<p><p>Bacterial pneumonia is the most common cause of acute respiratory distress syndrome (ARDS), characterized by disrupted pulmonary endothelial barrier function, hyperinflammation, and impaired alveolar epithelial fluid clearance. ARDS has a high mortality rate and no proven pharmacological treatments, stressing the need for new targeted therapies. The TIP peptide, mimicking the lectin-like domain of TNF, directly binds to the α subunit of the epithelial Na+ channel, expressed in both alveolar epithelial and capillary endothelial cells, and may increase lung endothelial barrier function and alveolar fluid clearance during bacterial infection. This study tested these potential therapeutic mechanisms of the TIP peptide in a clinically relevant preparation of the ex vivo-perfused human lung injured by Streptococcus pneumoniae. Therapeutic administration of the TIP peptide reduced pulmonary barrier permeability to protein and lung edema formation, increased alveolar edema fluid clearance, and produced an antiinflammatory effect in the airspaces with reductions in IL-6 and IL-8 levels. Additionally, the TIP peptide reduced the translocation of bacteria into the circulation. These findings establish 3 mechanisms of benefit with the TIP peptide to reduce injury in the human lung and support the clinical relevance as a potential therapeutic for pneumococcal bacterial pneumonia.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 11","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-09DOI: 10.1172/jci.insight.190648
Paul E George, Grace Kalmus, Joseph Lipscomb, David H Howard, Benjamin Kopp, Wilbur A Lam, Stefanie Ebelt
{"title":"Annual PM2.5 exposure and clinical, laboratory, and stroke-risk outcomes in pediatric sickle cell disease.","authors":"Paul E George, Grace Kalmus, Joseph Lipscomb, David H Howard, Benjamin Kopp, Wilbur A Lam, Stefanie Ebelt","doi":"10.1172/jci.insight.190648","DOIUrl":"https://doi.org/10.1172/jci.insight.190648","url":null,"abstract":"<p><p>Sickle cell disease (SCD) causes severe morbidity and early mortality, yet it varies phenotypically. Both air pollution and SCD affect the cardiorespiratory, inflammatory, and endothelial systems; however, limited evidence exists on the effect of long-term air pollution exposure in SCD. We hypothesized that annual ambient (outdoor) concentrations of fine particulate matter (PM2.5), particles with a diameter of 2.5 μm or less, at a child's home would be significantly associated with worse clinical, laboratory, and stroke-risk imaging outcomes. Patient data for this retrospective study were obtained from a cohort of children with SCD (from 2010 to 2019). Annual PM2.5 exposure was estimated using remote-sensing air pollution datasets. Statistical analyses employed fixed effects multivariable models, offering a robust approach to isolate the effect of PM2.5 exposure. The final cohort included 1,089 children with SCD. Higher annual PM2.5 concentrations were significantly associated with more annual hospital days, higher likelihood of hospitalization and abnormal stroke-risk screening, and elevated inflammatory markers. Of note, hydroxyurea use mitigated the inflammatory response to PM2.5 but did not mitigate the effect of PM2.5 on clinical outcomes. Importantly, the elevated stroke risk associated with PM2.5 exposure persisted, even among children receiving hydroxyurea therapy, highlighting a critical concern in pediatric SCD management. These results underscore the clinical importance of addressing environmental factors for comprehensive SCD care.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 11","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-09DOI: 10.1172/jci.insight.184843
Katie L Alexander, Kelsey B Bennion, Danya Liu, Mandy L Ford
{"title":"CD154:CD11b blockade enhances CD8+ T cell differentiation during infection but not transplantation.","authors":"Katie L Alexander, Kelsey B Bennion, Danya Liu, Mandy L Ford","doi":"10.1172/jci.insight.184843","DOIUrl":"https://doi.org/10.1172/jci.insight.184843","url":null,"abstract":"<p><p>CD154 is a promising target for immunosuppression in transplantation, autoimmunity, and inflammatory diseases. We previously identified CD11b as a novel alternative receptor for CD154 during alloimmunity. However, the impact of specific CD154:CD11b blockade on immune responses to infection has not been well characterized. Here, we have shown that in contrast with its immunosuppressive effect on graft-specific CD8+ T cells, CD154:CD11b blockade unexpectedly improved both the quantity and quality of murine herpesvirus-68-specific CD8+ T cells as measured by an increase in tetramer-positive KLRG1loCD127hi memory precursor effector cells. The differential effect of CD154:CD11b blockade on graft- versus virus-specific CD8+ T cells was underpinned by differences in phosphorylated S6 downstream of mTOR complex 1; however, differential expression of key transcription factors Eomes and TCF-1 was dictated by the type of antigen stimulus. These data demonstrate that priming conditions play an important role in determining the outcome of immunotherapy and suggest that specific inhibition of CD154:CD11b interactions could be effective for suppressing alloimmune responses while maintaining protective immunity to minimize infectious complications following transplantation.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 11","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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