The Journal of Clinical Investigation最新文献

{"title":"Timing of antiretroviral therapy initiation affects intact HIV reservoirs following analytical treatment interruption.","authors":"Maegan R Manning,Jana Blazkova,Jesse S Justement,Victoria Shi,Brooke D Kennedy,M Ali Rai,Catherine A Seamon,Kathleen Gittens,Michael C Sneller,Susan Moir,Tae-Wook Chun","doi":"10.1172/jci181632","DOIUrl":"https://doi.org/10.1172/jci181632","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TREM2 aggravates sepsis by inhibiting fatty acid oxidation via the SHP1/BTK axis.","authors":"Siqi Ming,Xingyu Li,Qiang Xiao,Siying Qu,Qiaohua Wang,Qiongyan Fang,Pingping Liang,Yating Xu,Jingwen Yang,Yongqiang Yang,Xi Huang,Yongjian Wu","doi":"10.1172/jci159400","DOIUrl":"https://doi.org/10.1172/jci159400","url":null,"abstract":"Impaired fatty acid oxidation (FAO) and the therapeutic benefits of FAO restoration have been revealed in sepsis. However, the regulatory factors contributing to FAO dysfunction during sepsis remain inadequately clarified. In this study, we identified a subset of lipid-associated macrophages characterized by high expression of trigger receptor expressed on myeloid cells 2 (TREM2) and demonstrated that TREM2 acted as a suppressor of FAO to increase the susceptibility to sepsis. TREM2 expression was markedly up-regulated in sepsis patients and correlated with the severity of sepsis. Knock out of TREM2 in macrophages improved the survival rate and reduced inflammation and organ injuries of sepsis mice. Notably, TREM2-deficient mice exhibited decreased triglyceride accumulation and an enhanced FAO rate. Further observations showed that the blockade of FAO substantially abolished the alleviated symptoms observed in TREM2 knockout mice. Mechanically, we demonstrated that TREM2 interacted with the phosphatase SHP1 to inhibit Bruton tyrosine kinas (BTK)-mediated FAO in sepsis. Our findings expand the understanding of FAO dysfunction in sepsis and reveal TREM2 as a critical regulator of FAO, which may provide a promising target for the clinical treatment of sepsis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EMC3 regulates trafficking and pulmonary toxicity of the SFTPCI73T mutation associated with interstitial lung disease.","authors":"Xiaofang Tang,Wei Wei,Yuqing Sun,Timothy E Weaver,Ernesto S Nakayasu,Geremy Clair,John M Snowball,Cheng-Lun Na,Karen S Apsley,Emily P Martin,Darrell N Kotton,Konstantinos-Dionysios Alysandratos,Jiuzhou Huo,Jeffery D Molkentin,William A Gower,Xinhua Lin,Jeffrey A Whitsett","doi":"10.1172/jci173861","DOIUrl":"https://doi.org/10.1172/jci173861","url":null,"abstract":"The most common mutation in surfactant protein C gene (SFTPC), SFTPCI73T, causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPCI73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity purification-mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including Valosin Containing Protein (VCP) and its interactors. Treatment of SftpcI73T knock-in mice and SFTPCI73T expressing iAT2 cells derived from SFTPCI73T patient-specific iPSCs with the specific VCP inhibitor CB5083 restored alveolar structure and SFTPCI73T trafficking respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPCI73T mutant, providing novel therapeutical targets for SFTPCI73T-associated interstitial lung disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcineurin inhibitor blocks tolerance by suppressing donor T cell terminal exhaustion after allogeneic hematopoietic cell transplantation.","authors":"Hajime Senjo,Daigo Hashimoto,Takanori Teshima","doi":"10.1172/jci184332","DOIUrl":"https://doi.org/10.1172/jci184332","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinguishing between help and harm: Helper T cell subsets and immune-related adverse events.","authors":"Alexandra M Haugh,Adil I Daud","doi":"10.1172/jci184310","DOIUrl":"https://doi.org/10.1172/jci184310","url":null,"abstract":"The precise conditions by which cytokines drive cancer is relevant to improving immune checkpoint inhibition (ICI) responses while decreasing toxicity. In this issue of the JCI, Kao et al. investigated T helper cell pathways in patients with solid tumors receiving ICI. The authors evaluated T cell populations, cytokine signatures, immune related adverse events (irAEs), and survival outcomes. Patients with a history of autoimmune disorders were more likely to develop irAEs. Notably, blood samples from patients on treatment showed that elevations in IL-5, IL-6, IL-17f, and TNF-α were associated with an increased risk for grade 2 or higher irAEs. Moreover, IL-6 was associated with decreased objective response rate and worse cancer-specific and all-cause mortality. These findings may help guide decisions for optimizing ICI efficacy while minimizing toxicity and suggest that IL-6 blockade may improve response and decrease toxicity in solid tumors.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.","authors":"Jonathan Bohlen,Ivan Bagarić,Taja Vatovec,Masato Ogishi,Syed F Ahmed,Axel Cederholm,Lori Buetow,Steicy Sobrino,Corentin Le Floc'h,Carlos A Arango-Franco,Luis Seabra,Marine Michelet,Federica Barzaghi,Davide Leardini,Francesco Saettini,Francesca Vendemini,Francesco Baccelli,Albert Catala,Eleonora Gambineri,Marinella Veltroni,Yurena Aguilar de la Red,Gillian I Rice,Filippo Consonni,Laureline Berteloot,Laetitia Largeaud,Francesca Conti,Cécile Roullion,Cécile Masson,Boris Bessot,Yoann Seeleuthner,Tom Le Voyer,Darawan Rinchai,Jérémie Rosain,Anna-Lena Neehus,Lucia Erazo-Borrás,Hailun Li,Zarah Janda,En-Jui Cho,Edoardo Muratore,Camille Soudée,Candice Lainé,Eric Delabesse,Claire Goulvestre,Cindy S Ma,Anne Puel,Stuart G Tangye,Isabelle André,Christine Bole-Feysot,Laurent Abel,Miriam Erlacher,Shen-Ying Zhang,Vivien Béziat,Chantal Lagresle-Peyrou,Emmanuelle Six,Marlène Pasquet,Laia Alsina,Alessandro Aiuti,Peng Zhang,Yanick J Crow,Nils Landegren,Riccardo Masetti,Danny T Huang,Jean-Laurent Casanova,Jacinta Bustamante","doi":"10.1172/jci181604","DOIUrl":"https://doi.org/10.1172/jci181604","url":null,"abstract":"Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HOPE springs eternal: lack of HIV superinfection in HIV Organ Policy Equity Act kidney transplants.","authors":"Christine M Durand,Andrew D Redd","doi":"10.1172/jci184326","DOIUrl":"https://doi.org/10.1172/jci184326","url":null,"abstract":"Kidney transplantation from donors with HIV to recipients with HIV (HIV D+/R+) is an emerging practice that has shown substantial clinical benefit. Sustained HIV superinfection, whereby a transplant recipient acquires a new strain of HIV from their organ donor, is a theoretical risk, which might increase chances of viral failure. In this issue of the JCI, Travieso, Stadtler, and colleagues present phylogenetic analysis of HIV from kidney tissue, urine, plasma, and cells from 12 HIV D+/R+ kidney transplants out to five years of follow-up. Early after transplant, donor HIV was transiently detected in five of 12 recipients, primarily from donors with untreated HIV and high-level viremia, consistent with a viral inoculum. Long-term, donor HIV was not detected in any recipients, demonstrating no sustained HIV superinfection. These reassuring data support earlier findings from South Africa and the United States and further confirm the safety of HIV D+/R+ transplantation.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conversations with JCI editors in chief.","authors":"Ushma S Neill","doi":"10.1172/jci187017","DOIUrl":"https://doi.org/10.1172/jci187017","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic therapies targeting histone lysine methylation: complex mechanisms and clinical challenges.","authors":"Sarah Gold,Ali Shilatifard","doi":"10.1172/jci183391","DOIUrl":"https://doi.org/10.1172/jci183391","url":null,"abstract":"As epigenetic therapies continue to gain ground as potential treatment strategies for cancer and other diseases, compounds that target histone lysine methylation and the enzyme complexes represent a major frontier for therapeutic development. Clinically viable therapies targeting the activities of histone lysine methyltransferases (HKMT) and demethylases (HKDMs) have only recently begun to emerge following FDA approval of the EZH2 inhibitor tazemetostat in 2020 and remain limited to compounds targeting the well-studied SET domain-containing HKMTs and their opposing HKDMs. These include the H3K27 methyltransferases EZH2/EZH1, the singular H3K79 methyltransferase DOT1L, and the H3K4 methyltransferase MLL1/COMPASS as well as H3K9 and H3K36 methyltransferases. They additionally include the H3K4/9-preferential demethylase LSD1 and the H3K4-, H3K27-, and H3K36-preferential KDM5, KDM6, and KDM2 demethylase subfamilies, respectively. This Review discusses the results of recent clinical and preclinical studies relevant to all of these existing and potential therapies. It provides an update on advancements in therapeutic development, as well as more basic molecular understanding, within the past 5 years approximately. It also offers a perspective on histone lysine methylation that departs from the long-predominant \"histone code\" metaphor, emphasizing complex-disrupting inhibitors and proximity-based approaches rather than catalytic domain inhibitors in the outlook for future therapeutic development.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An emerging multi-omic understanding of the genetics of opioid addiction.","authors":"Eric O Johnson,Heidi S Fisher,Kyle A Sullivan,Olivia Corradin,Sandra Sanchez-Roige,Nathan C Gaddis,Yasmine N Sami,Alice Townsend,Erica Teixeira Prates,Mirko Pavicic,Peter Kruse,Elissa J Chesler,Abraham A Palmer,Vanessa Troiani,Jason A Bubier,Daniel A Jacobson,Brion S Maher","doi":"10.1172/jci172886","DOIUrl":"https://doi.org/10.1172/jci172886","url":null,"abstract":"Opioid misuse, addiction, and associated overdose deaths remain global public health crises. Despite the tremendous need for pharmacological treatments, current options are limited in number, use, and effectiveness. Fundamental leaps forward in our understanding of the biology driving opioid addiction are needed to guide development of more effective medication-assisted therapies. This Review focuses on the omics-identified biological features associated with opioid addiction. Recent GWAS have begun to identify robust genetic associations, including variants in OPRM1, FURIN, and the gene cluster SCAI/PPP6C/RABEPK. An increasing number of omics studies of postmortem human brain tissue examining biological features (e.g., histone modification and gene expression) across different brain regions have identified broad gene dysregulation associated with overdose death among opioid misusers. Drawn together by meta-analysis and multi-omic systems biology, and informed by model organism studies, key biological pathways enriched for opioid addiction-associated genes are emerging, which include specific receptors (e.g., GABAB receptors, GPCR, and Trk) linked to signaling pathways (e.g., Trk, ERK/MAPK, orexin) that are associated with synaptic plasticity and neuronal signaling. Studies leveraging the agnostic discovery power of omics and placing it within the context of functional neurobiology will propel us toward much-needed, field-changing breakthroughs, including identification of actionable targets for drug development to treat this devastating brain disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}