JCI insightPub Date : 2025-05-13eCollection Date: 2025-06-23DOI: 10.1172/jci.insight.188175
Shany Picciotto, Camilo Arenas-Gallo, Amos Toren, Ruty Mehrian-Shai, Bryan Daly, Stephen Rhodes, Megan Prunty, Ruolin Liu, Anyull Bohorquez, Marta Grońska-Pęski, Shana Melanaphy, Pamela Callum, Emilie Lassen, Anne-Bine Skytte, Rebecca C Obeng, Christopher Barbieri, Molly Gallogly, Brenda Cooper, Katherine Daunov, Lydia Beard, Koen van Besien, Joshua Halpern, Quintin Pan, Gilad D Evrony, Viktor A Adalsteinsson, Jonathan E Shoag
{"title":"Chemotherapy and the somatic mutation burden of sperm.","authors":"Shany Picciotto, Camilo Arenas-Gallo, Amos Toren, Ruty Mehrian-Shai, Bryan Daly, Stephen Rhodes, Megan Prunty, Ruolin Liu, Anyull Bohorquez, Marta Grońska-Pęski, Shana Melanaphy, Pamela Callum, Emilie Lassen, Anne-Bine Skytte, Rebecca C Obeng, Christopher Barbieri, Molly Gallogly, Brenda Cooper, Katherine Daunov, Lydia Beard, Koen van Besien, Joshua Halpern, Quintin Pan, Gilad D Evrony, Viktor A Adalsteinsson, Jonathan E Shoag","doi":"10.1172/jci.insight.188175","DOIUrl":"10.1172/jci.insight.188175","url":null,"abstract":"<p><p>Many chemotherapeutic agents impair cancer growth by inducing DNA damage. The impact of these agents on mutagenesis in normal cells, including sperm, is largely unknown. Here, we applied high-fidelity duplex sequencing to 94 samples from 36 individuals exposed to diverse chemotherapies and 32 controls. We found that in many of the sperm samples from men exposed to chemotherapy, the mutation burden was elevated as compared with controls and the expected burden based on trio studies, with 1 patient having a more than 10-fold increase over that expected for age. Saliva from this same individual also had a markedly higher mutation burden. We then validated this finding using other tissues, also finding an increased mutation burden in the blood and liver of many patients exposed to chemotherapy as compared with unexposed controls. Similarly, mice treated with 3 cycles of cisplatin had an increased mutation burden in sperm but also in the liver and hematopoietic progenitor cells. These results suggest an association between cancer therapies and mutation burden, with implications for counseling patients with cancer considering banking sperm before therapy and for cancer survivors considering the trade-offs of using banked sperm as compared with conceiving naturally.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013940","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 : 2025-05-13eCollection Date: 2025-06-23DOI: 10.1172/jci.insight.188543
Elliott D SoRelle, Ellora Haukenfrers, Gillian Q Horn, Vaibhav Jain, James Giarraputo, Karen Abramson, Emily Hocke, Laura A Cooney, Kristina M Harris, Scott S Zamvil, Simon G Gregory, Micah A Luftig
{"title":"Early multiple sclerosis activity associated with TBX21+CD21loCXCR3+ B cell expansion resembling EBV-induced phenotypes.","authors":"Elliott D SoRelle, Ellora Haukenfrers, Gillian Q Horn, Vaibhav Jain, James Giarraputo, Karen Abramson, Emily Hocke, Laura A Cooney, Kristina M Harris, Scott S Zamvil, Simon G Gregory, Micah A Luftig","doi":"10.1172/jci.insight.188543","DOIUrl":"10.1172/jci.insight.188543","url":null,"abstract":"<p><p>Epstein-Barr virus (EBV) infection precedes multiple sclerosis (MS) onset and plays a poorly understood etiologic role. To investigate possible viral pathogenesis, we analyzed single-cell expression in peripheral B cells from people with early MS collected longitudinally during the Immune Tolerance Network STAyCIS Trial. Expression profiles were compared with single-cell RNA-Seq (scRNA-Seq) from in vitro EBV models, autoimmune disorders, chronic infectious diseases, and healthy controls. Analyses focused on CD19+CD20+CD21loCD11c+T-bet+ atypical B cells (ABCs). ABCs were significantly enriched in early MS PBMCs versus healthy controls by scRNA-Seq and flow cytometry, establishing ABC expansion as a clinical feature. EBV-associated ABC expression, including CXCR3, programmed cell death ligand 1 (PD-L1), and PD-L2, was enriched in early MS; however, direct EBV infection of ABCs was not detected. Early MS ABCs exhibited significantly upregulated inflammatory cytokine mRNAs (CXCL8, IL18, VEGFA). Further, de novo EBV-infected B cells secreted IL-8 and VEGF. MS activity stratification revealed rare, distinctive inflammatory ABCs significantly underrepresented in individuals with no evidence of activity long-term versus people with additional relapsing-remitting MS activity at the primary endpoint. Moreover, CXCR3+ ABCs increased after baseline diagnosis and were significantly enriched in people with disease exacerbation during the study. Thus, ABC expansion and inflammatory responses correlate to early MS activity, possibly as a bystander response to EBV.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010055","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 : 2025-05-08DOI: 10.1172/jci.insight.189480
Naomi Bryant, Lyndsey M Muehling, Kristin Wavell, W Gerald Teague, Judith A Woodfolk
{"title":"Rhinovirus as a driver of airway T cell dynamics in children with treatment-refractory recurrent wheeze.","authors":"Naomi Bryant, Lyndsey M Muehling, Kristin Wavell, W Gerald Teague, Judith A Woodfolk","doi":"10.1172/jci.insight.189480","DOIUrl":"10.1172/jci.insight.189480","url":null,"abstract":"<p><p>Severe asthma in children is notoriously difficult to treat, and its immunopathogenesis is complex. In particular, the contribution of T cells and relationships to antiviral immunity remain enigmatic. Here, we coupled deep phenotyping with machine learning methods to elucidate the dynamics of T cells in the lower airways of children with treatment-refractory recurrent wheeze, and examine rhinovirus (RV) as a driver. Our strategy revealed a T cell landscape dominated by type 1 and type 17 CD8+ signatures. Interrogation of phenotypic relationships coupled with trajectory mapping identified T cell migratory and differentiation pathways spanning the blood and airways that culminated in tissue residency, and involved transitions between type 1 and type 17 tissue-resident types. These dynamics were reflected in cytokine polyfunctionality. Use of machine learning tools to cross-compare T cell populations that were enriched in the airways of RV-positive children with those induced in the blood following experimental RV challenge precisely pinpointed RV-responsive signatures that contributed to T cell migratory and differentiation pathways. Despite their rarity, these signatures were also detected in the airways of RV-negative children. Together, our results underscore the aberrant nature of type 1 immunity in the airways of children with recurrent wheeze, and implicate an important viral trigger as a driver.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 9","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036047","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}
{"title":"Colonic inflammation triggers β cell proliferation during obesity development via a liver-to-pancreas interorgan mechanism.","authors":"Haremaru Kubo, Junta Imai, Tomohito Izumi, Masato Kohata, Yohei Kawana, Akira Endo, Hiroto Sugawara, Junro Seike, Takahiro Horiuchi, Hiroshi Komamura, Toshihiro Sato, Shinichiro Hosaka, Yoichiro Asai, Shinjiro Kodama, Kei Takahashi, Keizo Kaneko, Hideki Katagiri","doi":"10.1172/jci.insight.183864","DOIUrl":"10.1172/jci.insight.183864","url":null,"abstract":"<p><p>Under insulin-resistant conditions, such as obesity, pancreatic β cells adaptively proliferate and secrete more insulin to prevent blood glucose elevation. We previously reported hepatic ERK activation during obesity development to stimulate a neuronal relay system, consisting of afferent splanchnic nerves from the liver and efferent vagal nerves to the pancreas, thereby triggering adaptive β cell proliferation. However, the mechanism linking obesity with the interorgan system originating in hepatic ERK activation remains unclear. Herein, we clarified that colonic inflammation promotes β cell proliferation through this interorgan system from the liver to the pancreas. First, dextran sodium sulfate (DSS) treatment induced colonic inflammation and hepatic ERK activation as well as β cell proliferation, all of which were suppressed by blockades of the neuronal relay system by several approaches. In addition, treatment with anti-lymphocyte Peyer's patch adhesion molecule-1 (anti-LPAM1) antibody suppressed β cell proliferation induced by DSS treatment. Importantly, high-fat diet (HFD) feeding also elicited colonic inflammation, and its inhibition by anti-LPAM1 antibody administration suppressed hepatic ERK activation and β cell proliferation induced by HFD. Thus, colonic inflammation triggers adaptive β cell proliferation via the interorgan mechanism originating in hepatic ERK activation. The present study revealed a potentially novel role of the gastrointestinal tract in the maintenance of β cell regulation.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 9","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965927","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 : 2025-05-08eCollection Date: 2025-06-23DOI: 10.1172/jci.insight.183786
Ali K Jaafar, Aurélie Paulo-Ramos, Guillaume Rastoldo, Bryan Veeren, Cynthia Planesse, Matthieu Bringart, Philippe Rondeau, Kévin Chemello, Olivier Meilhac, Gilles C Lambert, Steeve Bourane
{"title":"PCSK9 deficiency promotes the development of peripheral neuropathy.","authors":"Ali K Jaafar, Aurélie Paulo-Ramos, Guillaume Rastoldo, Bryan Veeren, Cynthia Planesse, Matthieu Bringart, Philippe Rondeau, Kévin Chemello, Olivier Meilhac, Gilles C Lambert, Steeve Bourane","doi":"10.1172/jci.insight.183786","DOIUrl":"10.1172/jci.insight.183786","url":null,"abstract":"<p><p>Proprotein convertase subtilisin/kexin type 9 (PCSK9) induces the hepatic degradation of the low-density lipoprotein receptor (LDLR), thereby increasing the concentration of LDL-cholesterol in the blood. Beyond its effects on LDL, recent studies have reported pleiotropic effects of PCSK9, notably in septic shock, vascular inflammation, viral infection, and cancer. While the functional and structural integrity of peripheral nerves are critically influenced by circulating lipids, the effect of PCSK9 on the peripheral nervous system remains unknown. In this study, we investigated the consequences of PCSK9 deficiency on peripheral nerves. We found that PCSK9 deletion in mice leads to peripheral neuropathy, characterized by reduced thermal and mechanical pain sensations. PCSK9-deficient mice also presented with skin structural changes, including a reduction in nociceptive Schwann cell number, axonal swelling of Remak fibers, and hypomyelination of small nerve fibers. Interestingly, the peripheral nerves of PCSK9-deficient mice showed an upregulation of CD36, a fatty acid transporter, which correlated with increased nerve lipid content, structural mitochondrial abnormalities, and acylcarnitine accumulation. Our findings demonstrate that PCSK9 plays a critical role in peripheral nerves by regulating lipid homeostasis and that its deficiency results in symptoms related to peripheral neuropathy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013941","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 : 2025-05-08DOI: 10.1172/jci.insight.175188
Kate Williamson, Katie J Lee, Emma L Beamish, Alan Carter, Jade A Gumbs, Gabriella Cooper, Niamh S O'Heneghan-Yates, Lisa A Menezes, Graham Cheung, Daniel Brown, Rob Pettitt, Brendan Geraghty, Lucy A Bosworth, Eithne J Comerford, Peter D Clegg, Elizabeth G Canty-Laird
{"title":"Active synthesis of type I collagen homotrimer in Dupuytren's fibrosis is unaffected by anti-TNF-α treatment.","authors":"Kate Williamson, Katie J Lee, Emma L Beamish, Alan Carter, Jade A Gumbs, Gabriella Cooper, Niamh S O'Heneghan-Yates, Lisa A Menezes, Graham Cheung, Daniel Brown, Rob Pettitt, Brendan Geraghty, Lucy A Bosworth, Eithne J Comerford, Peter D Clegg, Elizabeth G Canty-Laird","doi":"10.1172/jci.insight.175188","DOIUrl":"10.1172/jci.insight.175188","url":null,"abstract":"<p><p>Dupuytren's disease is a common fibroproliferative disease of the palmar fascia of the hand, with advanced cases treated surgically. Anti-TNF injection has undergone phase 2 trials and may be effective in slowing early-stage disease progression. Here we sought to determine how new synthesis of type I collagen in Dupuytren's differs from normal palmar fascia samples and to analyze the role of TNF in aberrant collagen synthesis. Model nonfibrotic but fibrous connective tissues were used to analyze active type I collagen protein synthesis in development, aging, and degenerative disease, where it was restricted to early development and ruptured tissue. Dupuytren's tissue was shown to actively synthesize type I collagen, including abnormal type I collagen homotrimer. TNF-α reduced COL1A2 gene expression only in the presence of serum in 2D cell culture and had opposing effects on collagen protein production in the presence or absence of serum. TNF-α had only limited effects in 3D tendon-like constructs. Anti-TNF did not reduce type I collagen synthesis in 3D tendon-like constructs or prevent type I collagen homotrimer synthesis in Dupuytren's tissue. Hence, modulation of the TNF-α pathway in Dupuytren's disease is unlikely to prevent the pathological collagen accumulation that is characteristic of fibrosis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 9","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006967","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 : 2025-05-08eCollection Date: 2025-06-23DOI: 10.1172/jci.insight.180275
Ali Hashemi Gheinani, Bryan S Sack, Alexander Bigger-Allen, Hatim Thaker, Hussein Atta, George Lambrinos, Kyle Costa, Claire Doyle, Mehrnaz Gharaee-Kermani, Susan Patalano, Mary Piper, Justin F Cotellessa, Dijana Vitko, Haiying Li, Manubhai Kadayil Prabhakaran, Vivian Cristofaro, John Froehlich, Richard S Lee, Wei Yang, Maryrose P Sullivan, Jill A Macoska, Rosalyn M Adam
{"title":"Multiomics analysis unveils an inosine-sensitive DNA damage response in neurogenic bladder after spinal cord injury.","authors":"Ali Hashemi Gheinani, Bryan S Sack, Alexander Bigger-Allen, Hatim Thaker, Hussein Atta, George Lambrinos, Kyle Costa, Claire Doyle, Mehrnaz Gharaee-Kermani, Susan Patalano, Mary Piper, Justin F Cotellessa, Dijana Vitko, Haiying Li, Manubhai Kadayil Prabhakaran, Vivian Cristofaro, John Froehlich, Richard S Lee, Wei Yang, Maryrose P Sullivan, Jill A Macoska, Rosalyn M Adam","doi":"10.1172/jci.insight.180275","DOIUrl":"10.1172/jci.insight.180275","url":null,"abstract":"<p><p>Spinal cord injury (SCI) evokes profound dysfunction in hollow organs such as the urinary bladder and gut. Current treatments are limited by a lack of molecular data to inform novel therapeutic avenues. Previously, we showed that systemic treatment with the neuroprotective agent inosine improved bladder function following SCI in rats. Here, we applied integrated multi-omics analysis to explore molecular alterations in the bladder over time and their sensitivity to inosine following SCI. Canonical signaling pathways regulated by SCI included those associated with protein synthesis, neuroplasticity, wound healing, and neurotransmitter degradation. Upstream regulator and causal network analysis predicted multiple effectors of DNA damage response signaling following injury, including poly-ADP ribose phosphorylase-1 (PARP1). Markers of DNA damage (γH2AX, ATM/ATR substrates) and PARP activity were increased in bladder tissue following SCI and attenuated with inosine treatment. Inosine treatment also attenuated oxidative DNA damage in rat bladder cells in vitro. Proteomics analysis suggested that SCI induced changes in protein synthesis-, neuroplasticity-, and oxidative stress-associated pathways, a subset of which were shown in transcriptomics data to be inosine sensitive. These findings provide insights into the molecular landscape of the bladder following SCI and identify key inosine-sensitive pathways associated with injury.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019008","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 : 2025-05-08DOI: 10.1172/jci.insight.183076
Sarah A McNitt, Jenna K Dick, Maria Andrea Hernandez-Castaneda, Jules Sangala, Mark Pierson, Marissa Macchietto, Kristina S Burrack, Peter D Crompton, Karl Seydel, Sara E Hamilton, Geoffrey T Hart
{"title":"Phenotype and function of IL-10-producing NK cells in individuals with malaria experience.","authors":"Sarah A McNitt, Jenna K Dick, Maria Andrea Hernandez-Castaneda, Jules Sangala, Mark Pierson, Marissa Macchietto, Kristina S Burrack, Peter D Crompton, Karl Seydel, Sara E Hamilton, Geoffrey T Hart","doi":"10.1172/jci.insight.183076","DOIUrl":"10.1172/jci.insight.183076","url":null,"abstract":"<p><p>P.falciparum infection can trigger high levels of inflammation that lead to fever and sometimes severe disease. People living in malaria-endemic areas gradually develop resistance to symptomatic malaria and control both parasite numbers and the inflammatory response. We previously found that adaptive NK cells correlated with reduced parasite load and protection from symptoms. We also found that murine NK cell production of IL-10 protected mice from experimental cerebral malaria. Human NK cells can also secrete IL-10, but it is unknown what NK cell subsets produce IL-10 or if this is affected by malaria experience. We hypothesized that NK cell immunoregulation may lower inflammation and reduce fever induction. Here, we showed that NK cells from participants with malaria experience make significantly more IL-10 than participants with no malaria experience. We then determined the proportions of NK cells that are cytotoxic and produce IFN-γ and/or IL-10 and identified a signature of adaptive and checkpoint molecules on IL-10-producing NK cells. Lastly, we found that coculture with primary monocytes, Plasmodium-infected RBCs, and antibody induced IL-10 production by NK cells. These data suggest that NK cells may contribute to protection from malaria symptoms via IL-10 production.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 9","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006968","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 : 2025-05-08eCollection Date: 2025-06-09DOI: 10.1172/jci.insight.185975
Ya Deng, Jiaying Zhao, Chen Gong, Wenqian Ding, Lulu Fang, Huaqing Liu, Ming Li, Bing Shen, Shenggang Ding
{"title":"LRP1 regulates asthmatic airway smooth muscle proliferation through FGF2/ERK signaling.","authors":"Ya Deng, Jiaying Zhao, Chen Gong, Wenqian Ding, Lulu Fang, Huaqing Liu, Ming Li, Bing Shen, Shenggang Ding","doi":"10.1172/jci.insight.185975","DOIUrl":"10.1172/jci.insight.185975","url":null,"abstract":"<p><p>Airway smooth muscle (ASM) hyperplasia is a hallmark of airway remodeling in asthma, which still lacks an effective treatment. Low-density lipoprotein receptor-related protein 1 (LRP1) is involved in regulating the proliferation of various cell types, and the intracellular domain of LRP1 (LRP1-ICD) also exhibits unique biological functions. However, the role of LRP1 in asthma airway remodeling remains unclear. In the present study, LRP1 was increased in ASM cells of mice with OVA-induced chronic asthma, with the elevation in LRP1-ICD protein levels being significantly greater than that of the LRP1 β chain. In vivo experiments demonstrated that inhibiting LRP1 reduced ASM proliferation in these mice. Mechanistically, LRP1 knockdown inhibited the FGF2/ERK signaling pathway, thereby arresting cell cycle progression and suppressing ASM cell proliferation. Additionally, in vitro experiments revealed that the inhibitory effect of LRP1-ICD overexpression on ASM cell proliferation was lost after adjusting the levels of LRP1. LRP1-ICD overexpression inhibited full-length LRP1 protein levels by promoting its protein degradation rather than by suppressing its transcription, thus preventing further exacerbation of asthma. In conclusion, this study clarifies the molecular biological mechanism by which LRP1 regulates ASM proliferation, suggesting targeting full-length LRP1 as a strategy for therapeutic intervention in asthma airway remodeling.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024686","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 : 2025-05-08DOI: 10.1172/jci.insight.187911
Michael H Lee, Thaís C F Menezes, Julie A Reisz, Francesca I Cendali, Eloara V M Ferreira, Jaquelina S Ota-Arakaki, Priscila A Sperandio, Rahul Kumar, Claudia Mickael, Martin M Ieong, Juliana Lucena Santos, Ana Carolina B Duarte, Dara C Fonseca Balladares, Kevin Nolan, Rubin M Tuder, Paul M Hassoun, Angelo D'Alessandro, Rudolf K F Oliveira, Brian B Graham
{"title":"Physiologic relevance of the transpulmonary metabolome in connective tissue disease-associated pulmonary vascular disease.","authors":"Michael H Lee, Thaís C F Menezes, Julie A Reisz, Francesca I Cendali, Eloara V M Ferreira, Jaquelina S Ota-Arakaki, Priscila A Sperandio, Rahul Kumar, Claudia Mickael, Martin M Ieong, Juliana Lucena Santos, Ana Carolina B Duarte, Dara C Fonseca Balladares, Kevin Nolan, Rubin M Tuder, Paul M Hassoun, Angelo D'Alessandro, Rudolf K F Oliveira, Brian B Graham","doi":"10.1172/jci.insight.187911","DOIUrl":"10.1172/jci.insight.187911","url":null,"abstract":"<p><p>Pathologic implications of dysregulated pulmonary vascular metabolism to pulmonary arterial hypertension (PAH) are increasingly recognized, but their clinical applications have been limited. We hypothesized that metabolite quantification across the pulmonary vascular bed in connective tissue disease-associated (CTD-associated) PAH would identify transpulmonary gradients of pathobiologically relevant metabolites, in an exercise stage-specific manner. Sixty-three CTD patients with established or suspected PAH underwent exercise right heart catheterization. Using mass spectrometry-based metabolomics, metabolites were quantified in plasma samples simultaneously collected from the pulmonary and radial arteries at baseline and during resistance-free wheeling, peak exercise, and recovery. We identified uptake and excretion of metabolites across the pulmonary vascular bed, unique and distinct from single vascular site analysis. We demonstrated the physiological relevance of metabolites previously shown to promote disease in animal models and end-stage human lung tissues, including acylcarnitines, glycolytic intermediates, and tryptophan catabolites. Notably, pulmonary vascular metabolite handling was exercise stage specific. Transpulmonary metabolite gradients correlated with hemodynamic endpoints largely during free-wheeling. Glycolytic intermediates demonstrated physiologic significance at peak exercise, including net uptake of lactate in those with more advanced disease. Contribution of pulmonary vascular metabolism to CTD-PAH pathogenesis and therapeutic candidacy of metabolism modulation must be considered in the context of physiologic stress.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 9","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017224","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}
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