Journal of Clinical Investigation最新文献_第5页

Adding insult to injury: the spectrum of tubulointerstitial responses in acute kidney injury.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-17 DOI: 10.1172/JCI188358

Megan L Baker, Lloyd G Cantley

{"title":"Adding insult to injury: the spectrum of tubulointerstitial responses in acute kidney injury.","authors":"Megan L Baker, Lloyd G Cantley","doi":"10.1172/JCI188358","DOIUrl":"10.1172/JCI188358","url":null,"abstract":"Acute kidney injury (AKI) encompasses pathophysiology ranging from glomerular hypofiltration to tubular cell injury and outflow obstruction. This Review will focus on the tubulointerstitial processes that underlie most cases of AKI. Tubular epithelial cell (TEC) injury can occur via distinct insults, including ischemia, nephrotoxins, sepsis, and primary immune-mediated processes. Following these initial insults, tubular cells can activate survival and repair responses or they can develop mitochondrial dysfunction and metabolic reprogramming, cell-cycle arrest, and programmed cell death. Developing evidence suggests that the fate of individual tubular cells to survive and proliferate or undergo cell death or senescence is frequently determined by a biphasic immune response with initial proinflammatory macrophage, neutrophil, and lymphocyte infiltration exacerbating injury and activating programmed cell death, while alternatively activated macrophages and specific lymphocyte subsets subsequently modulate inflammation and promote repair. Functional recovery requires that this reparative phase supports proteolytic degradation of tubular casts, proliferation of surviving TECs, and restoration of TEC differentiation. Incomplete resolution or persistence of inflammation can lead to failed tubular repair, fibrosis, and chronic kidney disease. Despite extensive research in animal models, translating preclinical findings to therapies remains challenging, emphasizing the need for integrated multiomic approaches to advance AKI understanding and treatment.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 6","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648724","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}

引用次数: 0

The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-17 DOI: 10.1172/JCI191396

Xiang Chen, Jia Hu, Yunfei Wang, Younghee Lee, Xiaohong Zhao, Huiping Lu, Gengzhen Zhu, Hui Wang, Yu Jiang, Fan Liu, Yongzhen Chen, Byung-Seok Kim, Qinghua Zhou, Xindong Liu, Xiaohu Wang, Seon Hee Chang, Chen Dong

引用次数: 0

Genomic and transcriptomic profiling reveals distinct molecular subsets associated with outcomes in mantle cell lymphoma.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-17 DOI: 10.1172/JCI192372

Shuhua Yi, Yuting Yan, Meiling Jin, Supriyo Bhattacharya, Yi Wang, Yiming Wu, Lu Yang, Eva Gine, Guillem Clot, Lu Chen, Ying Yu, Dehui Zou, Jun Wang, An T Phan, Rui Cui, Fei Li, Qi Sun, Qiongli Zhai, Tingyu Wang, Zhen Yu, Lanting Liu, Wei Liu, Rui Lyv, Weiwei Sui, Wenyang Huang, Wenjie Xiong, Huijun Wang, Chengwen Li, Zhijian Xiao, Mu Hao, Jianxiang Wang, Tao Cheng, Silvia Bea, Alex F Herrera, Alexey Danilov, Elias Campo, Vu N Ngo, Lugui Qiu, Lili Wang

引用次数: 0

Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-17 DOI: 10.1172/JCI186889

Maude A Liegeois, Aileen Hsieh, May Al-Fouadi, Annabelle R Charbit, Chen Xi Yang, Tillie-Louise Hackett, John V Fahy

{"title":"Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence.","authors":"Maude A Liegeois, Aileen Hsieh, May Al-Fouadi, Annabelle R Charbit, Chen Xi Yang, Tillie-Louise Hackett, John V Fahy","doi":"10.1172/JCI186889","DOIUrl":"10.1172/JCI186889","url":null,"abstract":"BACKGROUNDMucus plugs form in acute asthma and persist in chronic disease. Although eosinophils are implicated in mechanisms of mucus pathology, many mechanistic details about mucus plug formation and persistence in asthma are unknown.METHODSUsing histology and spatial, single-cell proteomics, we characterized mucus-plugged airways from nontransplantable donor lungs of 14 patients with asthma (9 with fatal asthma and 5 with nonfatal asthma) and individuals acting as controls (10 with chronic obstructive pulmonary disease and 14 free of lung disease). Additionally, we used an airway epithelial cell-eosinophil (AEC-eosinophil) coculture model to explore how AEC mucus affects eosinophil degranulation.RESULTSAsthma mucus plugs were tethered to airways showing infiltration with innate lymphoid type 2 cells and hyperplasia of smooth muscle cells and MUC5AC-expressing goblet cells. Asthma mucus plugs were infiltrated with immune cells that were mostly dual positive for eosinophil peroxidase (EPX) and neutrophil elastase, suggesting that neutrophils internalize EPX from degranulating eosinophils. Indeed, eosinophils exposed to mucus from IL-13-activated AECs underwent CD11b- and glycan-dependent cytolytic degranulation. Dual-positive granulocytes varied in frequency in mucus plugs. Whereas paucigranulocytic plugs were MUC5AC rich, granulocytic plugs had a mix of MUC5AC, MUC5B, and extracellular DNA traps. Paucigranulocytic plugs occurred more frequently in (acute) fatal asthma and granulocytic plugs predominated in (chronic) nonfatal asthma.CONCLUSIONTogether, our data suggest that mucin-rich mucus plugs in fatal asthma form because of acute goblet cell degranulation in remodeled airways and that granulocytic mucus plugs in chronic asthma persist because of a sustaining niche characterized by epithelial cell-mucin-granulocyte cross-talk.FUNDINGNIH grants HL080414, HL107202, and AI077439.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 6","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648684","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}

引用次数: 0

Expanding the bandwidth of checkpoint inhibitors for cancer using epigenetic regulators.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-17 DOI: 10.1172/JCI188611

Daniel J Brat

引用次数: 0

Oncostatin M silence and neopeptide: the value of exploring patients with rare inherited bone marrow failure. 肿瘤抑制素 M 沉默和新肽：探索罕见遗传性骨髓衰竭患者的价值。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-17 DOI: 10.1172/JCI190955

Selket Delafontaine, Isabelle Meyts

{"title":"Oncostatin M silence and neopeptide: the value of exploring patients with rare inherited bone marrow failure.","authors":"Selket Delafontaine, Isabelle Meyts","doi":"10.1172/JCI190955","DOIUrl":"10.1172/JCI190955","url":null,"abstract":"Inherited bone marrow failure syndromes (IBMFSs) encompass a diverse group of hematological disorders characterized by a progressive single-lineage cytopenia or pancytopenia. Despite their heterogeneity, these syndromes often result from genetic errors affecting key biological mechanisms, including telomere maintenance, DNA repair and chromosomal stability, and ribosome assembly, generally leading to accelerated apoptosis of hematopoietic cells. Nevertheless, a genetic diagnosis remains elusive in more than half of the cases. The increased risk of myelodysplastic syndrome (MDS), acute leukemia, and solid tumors associated with IBMFS frequently prompts early hematopoietic stem cell transplantation (HSCT). In this issue of the JCI, Garrigue, Kermasson, and colleagues identified a homozygous variant in Oncostatin M (OSM) in 3 children from a consanguineous family presenting with IBMFS characterized by profound anemia, thrombocytopenia, and neutropenia. The findings suggest that the loss-of-function OSM variant affected hematopoietic stem cell function through changes to the bone marrow microenvironment (BMM).","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 6","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648836","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}

引用次数: 0

Sensing mycobacteria through unconventional pathways.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-17 DOI: 10.1172/JCI190230

Catarina F Almeida, Jennifer A Juno

引用次数: 0

Nonvesicular cholesterol transport in physiology.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-17 DOI: 10.1172/JCI188127

Alessandra Ferrari, Peter Tontonoz

引用次数: 0

Macrophages: key conductors behind perivascular inflammation and vascular remodeling in hypoxia-induced pulmonary hypertension.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-17 DOI: 10.1172/JCI190957

Edda Spiekerkoetter

{"title":"Macrophages: key conductors behind perivascular inflammation and vascular remodeling in hypoxia-induced pulmonary hypertension.","authors":"Edda Spiekerkoetter","doi":"10.1172/JCI190957","DOIUrl":"10.1172/JCI190957","url":null,"abstract":"Pulmonary hypertension (PH) encompasses a heterogenous group of disorders with the common feature of increased pulmonary arterial pressures. Patients with PH associated with lung disease and/or hypoxia undergo immune-mediated vascular remodeling that includes thickening of the muscular layer surrounding arteries and arterioles. In this issue of the JCI, Kumar and colleagues examined the role of interstitial macrophages in a model of high-altitude PH. Resident interstitial macrophages increased, proliferated, and expressed CCL2, a monocyte chemoattractant ligand. There was also a rise in CCR2+ macrophages expressing thrombospondin-1, which is known to activate vascular remodeling through TGF-β. Blocking monocyte recruitment partially reduced hypoxic PH, and corticosteroid treatment effectively reduced CCL2 expression and CCR2+ monocyte recruitment. Further, plasma samples collected from individuals ascending from low to high altitudes showed increased thrombospondin-1 and TGF-β levels, which were reduced with dexamethasone. These findings reveal interstitial macrophage populations as potential therapeutic targets in hypoxic PH.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 6","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648872","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}

引用次数: 0

Post-transfusion activation of coagulation pathways during severe COVID-19 correlates with COVID-19 convalescent plasma antibody profiles. 严重 COVID-19 期间输血后凝血途径的激活与 COVID-19 恢复期血浆抗体谱相关。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-17 DOI: 10.1172/JCI181136

Svenja Weiss, Hung-Mo Lin, Eric Acosta, Natalia L Komarova, Ping Chen, Dominik Wodarz, Ian Baine, Ralf Duerr, Ania Wajnberg, Adrian Gervais, Paul Bastard, Jean-Laurent Casanova, Suzanne A Arinsburg, Talia H Swartz, Judith A Aberg, Nicole M Bouvier, Sean Th Liu, Raymond A Alvarez, Benjamin K Chen

{"title":"Post-transfusion activation of coagulation pathways during severe COVID-19 correlates with COVID-19 convalescent plasma antibody profiles.","authors":"Svenja Weiss, Hung-Mo Lin, Eric Acosta, Natalia L Komarova, Ping Chen, Dominik Wodarz, Ian Baine, Ralf Duerr, Ania Wajnberg, Adrian Gervais, Paul Bastard, Jean-Laurent Casanova, Suzanne A Arinsburg, Talia H Swartz, Judith A Aberg, Nicole M Bouvier, Sean Th Liu, Raymond A Alvarez, Benjamin K Chen","doi":"10.1172/JCI181136","DOIUrl":"10.1172/JCI181136","url":null,"abstract":"Early antibody therapy can prevent severe SARS-CoV-2 infection (COVID-19). However, the effectiveness of COVID-19 convalescent plasma (CCP) therapy in treating severe COVID-19 remains inconclusive. To test a hypothesis that some CCP units are associated with a coagulopathy hazard in severe disease that offsets its benefits, we tracked 304 CCP units administered to 414 hospitalized COVID-19 patients to assess their association with the onset of unfavorable post-transfusion D-dimer trends. CCP recipients with increasing or persistently elevated D-dimer trajectories after transfusion experienced higher mortality than those whose D-dimer levels were persistently low or decreasing after transfusion. Within the CCP donor-recipient network, recipients with increasing or persistently high D-dimer trajectories were skewed toward association with a minority of CCP units. In in vitro assays, CCP from \"higher-risk\" units had higher cross-reactivity with the spike protein of human seasonal betacoronavirus OC43. \"Higher-risk\" CCP units also mediated greater Fcγ receptor IIa signaling against cells expressing SARS-CoV-2 spike compared with \"lower-risk\" units. This study finds that post-transfusion activation of coagulation pathways during severe COVID-19 is associated with specific CCP antibody profiles and supports a potential mechanism of immune complex-activated coagulopathy.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 6","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648838","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}

引用次数: 0