Journal of Clinical Investigation最新文献_第2页

Cxcr3 promotes protection from colorectal cancer liver metastasis by driving NK cell infiltration and plasticity.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI184036

Eleonora Russo, Chiara D'Aquino, Chiara Di Censo, Mattia Laffranchi, Luana Tomaipitinca, Valerio Licursi, Stefano Garofalo, Johann Promeuschel, Giovanna Peruzzi, Francesca Sozio, Anna Kaffke, Cecilia Garlanda, Ulf Panzer, Cristina Limatola, Christian A J Vosshenrich, Silvano Sozzani, Giuseppe Sciumè, Angela Santoni, Giovanni Bernardini

{"title":"Cxcr3 promotes protection from colorectal cancer liver metastasis by driving NK cell infiltration and plasticity.","authors":"Eleonora Russo, Chiara D'Aquino, Chiara Di Censo, Mattia Laffranchi, Luana Tomaipitinca, Valerio Licursi, Stefano Garofalo, Johann Promeuschel, Giovanna Peruzzi, Francesca Sozio, Anna Kaffke, Cecilia Garlanda, Ulf Panzer, Cristina Limatola, Christian A J Vosshenrich, Silvano Sozzani, Giuseppe Sciumè, Angela Santoni, Giovanni Bernardini","doi":"10.1172/JCI184036","DOIUrl":"https://doi.org/10.1172/JCI184036","url":null,"abstract":"The anti-metastatic activity of NK cells is well established in several cancer types, but the mechanisms underlying NK cell metastasis infiltration and acquisition of anti-tumor characteristics remain unclear. Herein, we investigated the cellular and molecular factors required to facilitate the generation of an ILC1-like CD49a+NK cell population within the liver metastasis (LM) environment of colorectal cancer (CRC). We show that CD49a+NK cells had the highest cytotoxic capacity among metastasis-infiltrating NK cells in the MC38 mouse model. Furthermore, the chemokine receptor CXCR3 promoted CD49a+NK cell accumulation and persistence in metastasis where NK cells co-localize with macrophages in CXCL9 and CXCL10 rich areas. By mining a published scRNA-seq dataset of a cohort of treatment-naïve CRC patients, we confirmed the accumulation of CXCR3+NK cells in metastatic samples. Conditional deletion of Cxcr3 in NKp46+ cells and antibody-mediated depletion of metastasis-associated macrophages impaired CD49a+NK cell development, indicating that CXCR3 and macrophages contribute to efficient NK cell localization and polarization in LM. Conversely, CXCR3neg NK cells maintained a CD49a- phenotype in metastasis with reduced parenchymal infiltration and tumor killing capacity. Furthermore, CD49a+NK cell accumulation was impaired in an independent SL4-induced CRC metastasis model, which fails to accumulate CXCL9+ macrophages. Together, our results highlight a role for CXCR3/ligand axis in promoting macrophage-dependent NK cell accumulation and functional sustenance in CRC LM.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764151","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}

引用次数: 0

Human genetics of metabolic dysfunction-associated steatotic liver disease: from variants to cause to precision treatment.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI186424

Vincent L Chen, Annapurna Kuppa, Antonino Oliveri, Yanhua Chen, Prabhu Ponnandy, Puja B Patel, Nicholette D Palmer, Elizabeth K Speliotes

{"title":"Human genetics of metabolic dysfunction-associated steatotic liver disease: from variants to cause to precision treatment.","authors":"Vincent L Chen, Annapurna Kuppa, Antonino Oliveri, Yanhua Chen, Prabhu Ponnandy, Puja B Patel, Nicholette D Palmer, Elizabeth K Speliotes","doi":"10.1172/JCI186424","DOIUrl":"https://doi.org/10.1172/JCI186424","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic disease and is a leading cause of advanced liver disease. We review here the genetic basis of MASLD. The genetic variants most consistently associated with hepatic steatosis implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, or mitochondrial/ER biology. The distinct mechanisms by which these variants promote hepatic steatosis result in distinct effects on cardiometabolic disease that may be best suited to precision medicine. Recent work on gene-environment interactions has shown that genetic risk is not fixed and may be exacerbated or attenuated by modifiable (diet, exercise, alcohol intake) and nonmodifiable environmental risk factors. Some steatosis-associated variants, notably those in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), are associated with risk of developing adverse liver-related outcomes and provide information beyond clinical risk stratification tools, especially in individuals at intermediate to high risk for disease. Future work to better characterize disease heterogeneity by combining genetics with clinical risk factors to holistically predict risk and develop therapies based on genetic risk is required.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 7","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752882","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}

引用次数: 0

HoxBlinc: a key driver of chromatin dynamics in NUP98 fusion-driven leukemia.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI191355

Jian Xu, Wei Du

引用次数: 0

Insights into protection against Mycobacterium tuberculosis infection: time to officially confirm another phenotype?

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI191423

Todia P Setiabudiawan, Philip C Hill, Andrew R DiNardo, Reinout van Crevel

引用次数: 0

Spermidine restricts neonatal inflammation via metabolic shaping of polymorphonuclear myeloid-derived suppressor cells.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI183559

Jiale Chen, Lin Zhu, Zhaohai Cui, Yuxin Zhang, Ran Jia, Dongmei Zhou, Bo Hu, Wei Zhong, Jin Xu, Lijuan Zhang, Pan Zhou, Wenyi Mi, Haitao Wang, Zhi Yao, Ying Yu, Qiang Liu, Jie Zhou

{"title":"Spermidine restricts neonatal inflammation via metabolic shaping of polymorphonuclear myeloid-derived suppressor cells.","authors":"Jiale Chen, Lin Zhu, Zhaohai Cui, Yuxin Zhang, Ran Jia, Dongmei Zhou, Bo Hu, Wei Zhong, Jin Xu, Lijuan Zhang, Pan Zhou, Wenyi Mi, Haitao Wang, Zhi Yao, Ying Yu, Qiang Liu, Jie Zhou","doi":"10.1172/JCI183559","DOIUrl":"https://doi.org/10.1172/JCI183559","url":null,"abstract":"Newborns exhibit a heightened vulnerability to inflammatory disorders due to their underdeveloped immune system, yet the underlying mechanisms remain poorly understood. Here we report that plasma spermidine is correlated with the maturity of human newborns and reduced risk of inflammation. Administration of spermidine led to the remission of neonatal inflammation in mice. Mechanistic studies revealed that spermidine enhanced the generation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) via downstream eIF5A hypusination. Genetic deficiency or pharmacological inhibition of deoxyhypusine synthase (DHPS), a key enzyme of hypusinated eIF5A (eIF5AHyp), diminished the immunosuppressive activity of PMN-MDSCs, leading to aggravated neonatal inflammation. The eIF5AHyp pathway was found to enhance the immunosuppressive function via histone acetylation-mediated epigenetic transcription of immunosuppressive signatures in PMN-MDSCs. These findings demonstrate the spermidine-eIF5AHyp metabolic axis as a master switch to restrict neonatal inflammation.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 7","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752917","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}

引用次数: 0

Unveiling the cholesterol-hemangioma axis: a path to new treatments.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI193039

M Luisa Iruela-Arispe

引用次数: 0

TRIB3 mediates vascular calcification by facilitating self-ubiquitination and dissociation of Smurf1 in chronic kidney disease.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-04-01 DOI: 10.1172/JCI175972

Yihui Li, Chang Ma, Yanan Sheng, Shanying Huang, Huaibing Sun, Yun Ti, Zhihao Wang, Feng Wang, Fangfang Chen, Chen Li, Haipeng Guo, Mengxiong Tang, Fangqiang Song, Hao Wang, Ming Zhong

{"title":"TRIB3 mediates vascular calcification by facilitating self-ubiquitination and dissociation of Smurf1 in chronic kidney disease.","authors":"Yihui Li, Chang Ma, Yanan Sheng, Shanying Huang, Huaibing Sun, Yun Ti, Zhihao Wang, Feng Wang, Fangfang Chen, Chen Li, Haipeng Guo, Mengxiong Tang, Fangqiang Song, Hao Wang, Ming Zhong","doi":"10.1172/JCI175972","DOIUrl":"10.1172/JCI175972","url":null,"abstract":"The osteogenic environment promotes vascular calcium phosphate deposition and aggregation of unfolded and misfolded proteins, resulting in ER stress in chronic kidney disease (CKD). Controlling ER stress through genetic intervention is a promising approach for treating vascular calcification. In this study, we demonstrated a positive correlation between ER stress-induced tribble homolog 3 (TRIB3) expression and progression of vascular calcification in human and rodent CKD. Increased TRIB3 expression promoted vascular smooth muscle cell (VSMC) calcification by interacting with the C2 domain of the E3 ubiquitin-protein ligase Smurf1, facilitating its K48-related self-ubiquitination at Lys381 and Lys383 and subsequent dissociation from the plasma membrane and nuclei. This degeneration of Smurf1 accelerated the stabilization of the osteogenic transcription factors RUNX family transcription factor 2 (Runx2) and SMAD family member 1 (Smad1). C/EBP homologous protein and activating transcription factor 4 are upstream transcription factors of TRIB3 in an osteogenic environment. Genetic KO of TRIB3 or rescue of Smurf1 ameliorated VSMC and vascular calcification by stabilizing Smurf1 and enhancing the degradation of Runx2 and Smad1. Our findings shed light on the vital role of TRIB3 as a scaffold in ER stress and vascular calcification and offer a potential therapeutic option for CKD.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399415","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

Epigenetic alteration of smooth muscle cells regulates endothelin-dependent blood pressure and hypertensive arterial remodeling.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-27 DOI: 10.1172/JCI186146

Kevin D Mangum, Qinmengge Li, Katherine Hartmann, Tyler M Bauer, Sonya J Wolf, James Shadiow, Jadie Y Moon, Emily Barrett, Amrita Joshi, Gabriela Saldana de Jimenez, Sabrina A Rocco, Zara Ahmed, Rachael Bogle, Kylie Boyer, Andrea Obi, Frank M Davis, Lin Chang, Lam Tsoi, Johann Gudjonsson, Scott M Damrauer, Katherine Gallagher

{"title":"Epigenetic alteration of smooth muscle cells regulates endothelin-dependent blood pressure and hypertensive arterial remodeling.","authors":"Kevin D Mangum, Qinmengge Li, Katherine Hartmann, Tyler M Bauer, Sonya J Wolf, James Shadiow, Jadie Y Moon, Emily Barrett, Amrita Joshi, Gabriela Saldana de Jimenez, Sabrina A Rocco, Zara Ahmed, Rachael Bogle, Kylie Boyer, Andrea Obi, Frank M Davis, Lin Chang, Lam Tsoi, Johann Gudjonsson, Scott M Damrauer, Katherine Gallagher","doi":"10.1172/JCI186146","DOIUrl":"10.1172/JCI186146","url":null,"abstract":"Long-standing hypertension (HTN) affects multiple organs and leads to pathologic arterial remodeling, which is driven by smooth muscle cell (SMC) plasticity. To identify relevant genes regulating SMC function in HTN, we considered Genome Wide Association Studies (GWAS) of blood pressure, focusing on genes encoding epigenetic enzymes, which control SMC fate in cardiovascular disease. Using statistical fine mapping of the KDM6 (JMJD3) locus, we found that rs62059712 is the most likely casual variant, with each major T allele copy associated with a 0.47 mmHg increase in systolic blood pressure. We show that the T allele decreased JMJD3 transcription in SMCs via decreased SP1 binding to the JMJD3 promoter. Using our unique SMC-specific Jmjd3-deficient murine model (Jmjd3flox/floxMyh11CreERT), we show that loss of Jmjd3 in SMCs results in HTN due to decreased EDNRB expression and increased EDNRA expression. Importantly, the Endothelin Receptor A antagonist, BQ-123, reversed HTN after Jmjd3 deletion in vivo. Additionally, single cell RNA-sequencing (scRNA-seq) of human arteries revealed strong correlation between JMJD3 and EDNRB in SMCs. Further, JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs increased HTN-induced arterial remodeling. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing targets that may be used in personalized management of HTN.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719367","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}

引用次数: 0

Prefrontal correlates of fear generalization during endocannabinoid depletion.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-27 DOI: 10.1172/JCI179881

Luis E Rosas-Vidal, Saptarnab Naskar, Leah M Mayo, Irene Perini, Rameen Masroor, Megan Altemus, Liorimar Ramos-Medina, S Danyal Zaidi, Hilda Engelbrektsson, Puja Jagasia, Markus Heilig, Sachin Patel

{"title":"Prefrontal correlates of fear generalization during endocannabinoid depletion.","authors":"Luis E Rosas-Vidal, Saptarnab Naskar, Leah M Mayo, Irene Perini, Rameen Masroor, Megan Altemus, Liorimar Ramos-Medina, S Danyal Zaidi, Hilda Engelbrektsson, Puja Jagasia, Markus Heilig, Sachin Patel","doi":"10.1172/JCI179881","DOIUrl":"10.1172/JCI179881","url":null,"abstract":"Maladaptive fear generalization is one of the hallmarks of trauma-related disorders. The endocannabinoid 2-arachidonoylglycerol (2-AG) is crucial for modulating anxiety, fear, and stress adaptation but its role in balancing fear discrimination versus generalization is not known. To address this, we used a combination of plasma endocannabinoid measurement and neuroimaging from a childhood maltreatment-exposed and non-exposed mixed population combined with human and rodent fear conditioning models. Here we show that 2-AG levels are inversely associated with fear generalization at the behavioral level in both mice and humans. In mice, 2-AG depletion increases the proportion of neurons, and the similarity between neuronal representations, of threat-predictive and neutral stimuli within prelimbic prefrontal cortex neuronal ensembles. In humans, increased dorsolateral prefrontal cortical-amygdala resting state connectivity is inversely correlated with fear generalization. These data provide convergent cross-species evidence that 2-AG is a key regulator of fear generalization and further support the notion that 2-AG deficiency could represent a trauma-related disorder susceptibility endophenotype.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719369","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}

引用次数: 0

Bacterial vaginosis associates with dysfunctional T cells and altered soluble immune factors in the cervicovaginal tract.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-25 DOI: 10.1172/JCI184609

Finn MacLean, Adino Tesfahun Tsegaye, Jessica B Graham, Jessica L Swarts, Sarah C Vick, Nicole B Potchen, Irene Cruz Talavera, Lakshmi Warrier, Julien Dubrulle, Lena K Schroeder, Ayumi Saito, Corinne Mar, Katherine K Thomas, Matthias Mack, Michelle C Sabo, Bhavna H Chohan, Kenneth Ngure, Nelly Rwamba Mugo, Jairam R Lingappa, Jennifer M Lund

{"title":"Bacterial vaginosis associates with dysfunctional T cells and altered soluble immune factors in the cervicovaginal tract.","authors":"Finn MacLean, Adino Tesfahun Tsegaye, Jessica B Graham, Jessica L Swarts, Sarah C Vick, Nicole B Potchen, Irene Cruz Talavera, Lakshmi Warrier, Julien Dubrulle, Lena K Schroeder, Ayumi Saito, Corinne Mar, Katherine K Thomas, Matthias Mack, Michelle C Sabo, Bhavna H Chohan, Kenneth Ngure, Nelly Rwamba Mugo, Jairam R Lingappa, Jennifer M Lund","doi":"10.1172/JCI184609","DOIUrl":"https://doi.org/10.1172/JCI184609","url":null,"abstract":"Background: Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that is prevalent among reproductive-age females worldwide. Adverse health outcomes associated with BV include an increased risk of sexually-acquired HIV, yet the immunological mechanisms underlying this association are not well understood.Methods: To investigate BV-driven changes to cervicovaginal tract (CVT) and circulating T cell phenotypes, Kinga Study participants with or without BV provided vaginal tract (VT) and ectocervical (CX) tissue biopsies and PBMC samples.Results: High-parameter flow cytometry revealed an increased frequency of cervical conventional CD4+ T cells (Tconv) expressing CCR5. However, we found no difference in number of CD3+CD4+CCR5+ cells in the CX or VT of BV+ versus BV- individuals, suggesting that BV-driven increased HIV susceptibility may not be solely attributed to increased CVT HIV target cell abundance. Flow cytometry also revealed that individuals with BV have an increased frequency of dysfunctional CX and VT CD39+ Tconv and CX tissue-resident CD69+CD103+ Tconv, reported to be implicated in HIV acquisition risk and replication. Many soluble immune factor differences in the CVT further support that BV elicits diverse and complex CVT immune alterations.Conclusion: Our comprehensive analysis expands on potential immunological mechanisms that may underlie the adverse health outcomes associated with BV including increased HIV susceptibility.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710178","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}

引用次数: 0