The Journal of Clinical Investigation最新文献_第2页

Allergens abrogate anti-inflammatory DNA effects and unmasks macrophage-driven neutrophilic asthma via ILC2/STING/TNF signaling. 过敏原通过ILC2/STING/TNF信号通路消除抗炎DNA作用，揭露巨噬细胞驱动的嗜中性粒细胞哮喘。

The Journal of Clinical Investigation Pub Date : 2025-06-17 DOI: 10.1172/jci187907

Anand Sripada,Divya Verma,Rangati Varma,Kapil Sirohi,Carolyn Kwiat,Mohini Pathria,Mukesh Verma,Anita Sahu,Vamsi P Guntur,Laurie A Manka,Brian Vestal,Camille M Moore,Richard J Martin,Magdalena M Gorska,John Cambier,Andrew Getahun,Rafeul Alam

{"title":"Allergens abrogate anti-inflammatory DNA effects and unmasks macrophage-driven neutrophilic asthma via ILC2/STING/TNF signaling.","authors":"Anand Sripada,Divya Verma,Rangati Varma,Kapil Sirohi,Carolyn Kwiat,Mohini Pathria,Mukesh Verma,Anita Sahu,Vamsi P Guntur,Laurie A Manka,Brian Vestal,Camille M Moore,Richard J Martin,Magdalena M Gorska,John Cambier,Andrew Getahun,Rafeul Alam","doi":"10.1172/jci187907","DOIUrl":"https://doi.org/10.1172/jci187907","url":null,"abstract":"The mechanism of neutrophilic and mixed neutrophilic-eosinophilic asthma is poorly understood. We found that extracellular DNA and nucleosomes (Nuc) were elevated in the airways from neutrophilic-eosinophilic asthma patients and correlated with bronchoalveolar lavage neutrophils. Bronchial tissue from neutrophilic-eosinophilic asthma expressed increased DNA sensor-positive cells. Intranasally administered DNA did not induce airway hyperreactivity (AHR) or any pathology but induced AHR and neutrophilic-eosinophilic inflammation when co- administered with the allergen Alternaria (Alt). Nuc alone induced anti-inflammatory/defensive genes whereas the Nuc-Alt combo increased TNF and innate cytokines. The Alt-Nuc phenotype was abolished in Cgas-/-, ALR-/-, Sting-/-, LysMCre:Stingf/f, IL7RCre:Rorαf/f and Tnfr2-/- mice. Alt, unexpectedly, played an essential role in the Nuc-induced phenotype. It abrogated Nuc-induction of anti-inflammatory genes, facilitated Nuc uptake, induced ILC2s, which, in presence of Nuc, produced high levels of TNFα and promoted neutrophilic infiltration. We established a paradigm where allergens inhibit the anti-inflammatory effects of DNA/Nuc and facilitate STING-TNFα-driven neutrophilic-eosinophilic inflammation in asthma.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"623 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311426","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}

引用次数: 0

E3 ubiquitin ligase Listerin regulates macrophage cholesterol efflux and atherosclerosis by targeting ABCA1. E3泛素连接酶Listerin通过靶向ABCA1调控巨噬细胞胆固醇外排和动脉粥样硬化。

The Journal of Clinical Investigation Pub Date : 2025-06-17 DOI: 10.1172/jci186509

Lei Cao,Jie Zhang,Liwen Yu,Wei Yang,Wenqian Qi,Ruiqing Ren,Yapeng Liu,Yonghao Hou,Yu Cao,Qian Li,Xiaohong Wang,Zhengguo Zhang,Bo Li,Wenhai Sui,Yun Zhang,Chengjiang Gao,Cheng Zhang,Meng Zhang

{"title":"E3 ubiquitin ligase Listerin regulates macrophage cholesterol efflux and atherosclerosis by targeting ABCA1.","authors":"Lei Cao,Jie Zhang,Liwen Yu,Wei Yang,Wenqian Qi,Ruiqing Ren,Yapeng Liu,Yonghao Hou,Yu Cao,Qian Li,Xiaohong Wang,Zhengguo Zhang,Bo Li,Wenhai Sui,Yun Zhang,Chengjiang Gao,Cheng Zhang,Meng Zhang","doi":"10.1172/jci186509","DOIUrl":"https://doi.org/10.1172/jci186509","url":null,"abstract":"Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA sequencing, we identified Listerin as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific knockout mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxLDL. ABCA1 agonist Erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while ABCA1 knockout abolished Listerin's effects in THP-1 cells. This study establishes Listerin as a protective factor in atherosclerosis via post-translational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311468","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}

引用次数: 0

CNS-targeted base editing of the major late-onset Tay-Sachs mutation alleviates disease in mice. 针对cns的主要晚发性Tay-Sachs突变的碱基编辑减轻了小鼠的疾病。

The Journal of Clinical Investigation Pub Date : 2025-06-17 DOI: 10.1172/jci183434

Maria L Allende,Mari Kono,Y Terry Lee,Samantha M Olmsted,Vienna Huso,Jenna Y Bakir,Florencia Pratto,Cuiling Li,Colleen Byrnes,Galina Tuymetova,Hongling Zhu,Cynthia J Tifft,Richard L Proia

{"title":"CNS-targeted base editing of the major late-onset Tay-Sachs mutation alleviates disease in mice.","authors":"Maria L Allende,Mari Kono,Y Terry Lee,Samantha M Olmsted,Vienna Huso,Jenna Y Bakir,Florencia Pratto,Cuiling Li,Colleen Byrnes,Galina Tuymetova,Hongling Zhu,Cynthia J Tifft,Richard L Proia","doi":"10.1172/jci183434","DOIUrl":"https://doi.org/10.1172/jci183434","url":null,"abstract":"Late-onset Tay-Sachs (LOTS) disease is a lysosomal storage disorder most commonly caused by a point mutation (c.805G>A) in the HEXA gene encoding the α-subunit of the lysosomal enzyme β-hexosaminidase A. LOTS manifests as a range of gradually worsening neurological symptoms beginning in young adulthood. Here, we explored the efficacy of an adenine base editor (ABE) programmed with a small guide RNA (sgRNA) to correct the HEXA c.805G>A mutation. Base editing in LOTS patient fibroblasts successfully converted the pathogenic HEXA c.805A to G and partially restored β-hexosaminidase activity, with minimal genome-wide off-target editing. We generated a LOTS mouse model in which the mice exhibited decreased β-hexosaminidase activity, accumulation of GM2 ganglioside in the brain, progressive neurological manifestations, and reduced lifespan. Treatment of LOTS mice with the neurotropic virus AAV-PHP.eB carrying the ABE and an sgRNA targeting the LOTS point mutation partially corrected the c.805G>A mutation in the CNS, significantly increased brain β-hexosaminidase activity, and substantially reduced GM2 ganglioside accumulation in the brain. Moreover, the therapy delayed symptom onset and significantly extended median lifespan. These findings highlight the potential of base editing as an effective treatment for LOTS and its broader applicability to other lysosomal storage disorders.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311467","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}

引用次数: 0

The secret life of complement: challenges and opportunities in exploring functions of the complosome in disease. 补体的秘密生命：探索复合体在疾病中的功能的挑战与机遇。

The Journal of Clinical Investigation Pub Date : 2025-06-16 DOI: 10.1172/jci188350

Tilo Freiwald,Behdad Afzali

{"title":"The secret life of complement: challenges and opportunities in exploring functions of the complosome in disease.","authors":"Tilo Freiwald,Behdad Afzali","doi":"10.1172/jci188350","DOIUrl":"https://doi.org/10.1172/jci188350","url":null,"abstract":"The complement system is a highly conserved and essential immune component with pivotal roles in innate and adaptive immunity. It is increasingly recognized that the complement system has a profound impact on disease. Current complement-targeting therapeutics for clinical use almost exclusively target the complement system in circulation. However, recent discoveries have demonstrated that complement is not only liver derived and plasma operative, but also synthesized and activated inside many cells locally within tissues, performing noncanonical, cell-autonomous intracellular functions, collectively referred to as the complosome. These intracellular complement pathways are distinct from the classical plasma-based system and critical for regulating fundamental cellular processes, including metabolism, gene transcription, autophagy, and the activation and resolution of inflammation. This Review explores the emerging roles of the complosome and current knowledge regarding its relation to human diseases, highlighting evidence across organ systems and disease states, including the kidneys, digestive tract, lungs, heart, CNS, musculoskeletal system, skin, and cancer. We also review current scientific approaches for detecting and functionally investigating the complosome, addressing challenges such as technological limitations and the need for advanced experimental models to delineate its tissue-specific roles. Finally, we discuss central unanswered questions critical for developing innovative therapeutic strategies targeting intracellular complement pathways. These strategies hold potential to modulate disease-specific mechanisms while preserving systemic complement activity.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295961","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}

引用次数: 0

Hemodynamic forces prevent myxomatous valve disease in mice through KLF2/4 signaling. 血流动力学力通过KLF2/4信号传导预防小鼠粘液瘤瓣膜病。

The Journal of Clinical Investigation Pub Date : 2025-06-16 DOI: 10.1172/jci186593

Jesse A Pace,Lauren M Goddard,Courtney C Hong,Liqing Wang,Jisheng Yang,Mei Chen,Yitian Xu,Martin H Dominguez,Siqi Gao,Xiaowen Chen,Patricia Mericko-Ishizuka,Can Tan,Tsutomu Kume,Wenbao Yu,Kai Tan,Wayne W Hancock,Giovanni Ferrari,Mark L Kahn

{"title":"Hemodynamic forces prevent myxomatous valve disease in mice through KLF2/4 signaling.","authors":"Jesse A Pace,Lauren M Goddard,Courtney C Hong,Liqing Wang,Jisheng Yang,Mei Chen,Yitian Xu,Martin H Dominguez,Siqi Gao,Xiaowen Chen,Patricia Mericko-Ishizuka,Can Tan,Tsutomu Kume,Wenbao Yu,Kai Tan,Wayne W Hancock,Giovanni Ferrari,Mark L Kahn","doi":"10.1172/jci186593","DOIUrl":"https://doi.org/10.1172/jci186593","url":null,"abstract":"Myxomatous valve disease (MVD) is the most common form of cardiac valve disease in the developed world. A small fraction of MVD is syndromic and arises in association with matrix protein defects such as those in Marfan syndrome, but most MVD is acquired later in life through an undefined pathogenesis. The KLF2/4 transcription factors mediate endothelial fluid shear responses, including those required to create cardiac valves during embryonic development. Here we test the role of hemodynamic shear forces and downstream endothelial KLF2/4 in mature cardiac valves. We find that loss of hemodynamic forces in heterotopically transplanted hearts or genetic deletion of KLF2/4 in cardiac valve endothelium confers valve cell proliferation and matrix deposition associated with valve thickening, findings also observed in mice expressing the mutant fibrillin-1 protein known to cause human MVD. Transcriptomic and histologic analysis reveals increased monocyte recruitment and TGF-β signaling in both fibrillin-1-mutant valves and valves lacking hemodynamic forces or endothelial KLF2/4 function, but only loss of TGF-β/SMAD signaling rescued myxomatous changes. We observed reduced KLF2/4 expression and augmented SMAD signaling in human MVD. These studies identify hemodynamic activation of endothelial KLF2/4 as an environmental homeostatic regulator of cardiac valves and suggest that non-syndromic MVD may arise in association with disturbed blood flow across the aging valve.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"228 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295963","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}

引用次数: 0

Role of local complement activation in kidney fibrosis and repair. 局部补体激活在肾纤维化和修复中的作用。

The Journal of Clinical Investigation Pub Date : 2025-06-16 DOI: 10.1172/jci188345

Didier Portilla,Vikram Sabapathy,Daniel Chauss

{"title":"Role of local complement activation in kidney fibrosis and repair.","authors":"Didier Portilla,Vikram Sabapathy,Daniel Chauss","doi":"10.1172/jci188345","DOIUrl":"https://doi.org/10.1172/jci188345","url":null,"abstract":"The complement system is an important component of the innate immune system involved in host defense and maintaining homeostasis. While the liver is the main source of complement proteins in the bloodstream, recent research has shown that various tissues, including the kidneys, can produce complement components locally in response to both acute and chronic inflammation. This Review highlights evidence from animal models of glomerular and tubulointerstitial kidney disease showing increased expression of intracellular complement in the kidneys. Studies using knockout mice for complement and complement receptors, along with complement inhibitors, have demonstrated that reduced complement activation in animal models of kidney fibrosis led to reduced inflammation and fibrosis, thereby supporting the pathogenic role of complement activation. Data from single-cell RNA-sequencing, spatial transcriptomics, and proteomics studies further demonstrate that alterations in local complement levels contribute to the fibrotic microenvironment observed in these models. Additionally, kidney biopsy results from patients with acute kidney injury and chronic kidney disease (CKD) indicate an increased expression of intracellular complement components as disease progresses. Developing drugs aimed at diminishing the expression and activation of local complement in glomerular and tubulointerstitial kidney disease could provide a novel approach to managing CKD.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295965","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}

引用次数: 0

Microglia matters: visualizing the immune battle in Parkinson's disease. 小胶质细胞很重要：观察帕金森病的免疫战。

The Journal of Clinical Investigation Pub Date : 2025-06-16 DOI: 10.1172/jci192919

So Jeong Lee,Changning Wang,Jacob Hooker

引用次数: 0

Should GLP-1 receptor agonist therapy be used to treat obesity in Bardet-Biedl syndrome? 是否应该使用GLP-1受体激动剂治疗Bardet-Biedl综合征的肥胖？

The Journal of Clinical Investigation Pub Date : 2025-06-16 DOI: 10.1172/jci191822

Jeremy W Tomlinson

引用次数: 0

Uromodulin modulates mitochondria and kidney tubule resilience. 尿调素调节线粒体和肾小管弹性。

The Journal of Clinical Investigation Pub Date : 2025-06-16 DOI: 10.1172/jci193829

Ronak Lakhia,Chunzi Song,Vishal Patel

引用次数: 0

RSK1-driven TRIM28/E2F1 feedback loop promotes castration-resistant prostate cancer progression. rsk1驱动的TRIM28/E2F1反馈回路促进去势抵抗性前列腺癌的进展。

The Journal of Clinical Investigation Pub Date : 2025-06-16 DOI: 10.1172/jci185119

Miyeong Kim,Jinpeng Liu,Yanquan Zhang,Ruixin Wang,Ryan Goettl,Jennifer Grasso,Derek B Allison,Chi Wang,Tianyan Gao,Xiaoqi Liu,Ka-Wing Fong

{"title":"RSK1-driven TRIM28/E2F1 feedback loop promotes castration-resistant prostate cancer progression.","authors":"Miyeong Kim,Jinpeng Liu,Yanquan Zhang,Ruixin Wang,Ryan Goettl,Jennifer Grasso,Derek B Allison,Chi Wang,Tianyan Gao,Xiaoqi Liu,Ka-Wing Fong","doi":"10.1172/jci185119","DOIUrl":"https://doi.org/10.1172/jci185119","url":null,"abstract":"Castration-resistant prostate cancer (CRPC) marks the advanced and lethal stage of prostate cancer (PCa). TRIM28, also known as KAP1, is a transcriptional regulator recently shown to promote CRPC cell proliferation and xenograft tumor growth. Nonetheless, knowledge gaps persist regarding the mechanisms underlying TRIM28 upregulation in CRPC as well as the genomic targets regulated by TRIM28. Here, we report that TRIM28 is a E2F1 target in CRPC. Using an integrated genomic approach, we have demonstrated that TRIM28 forms a positive feedback loop to promote the transcriptional activation and genomic function of E2F1 independent of retinoblastoma (Rb) status. Furthermore, we identified RSK1 as a kinase that directly phosphorylates TRIM28 at S473, and, as such, RSK1 drives the TRIM28/E2F1 feedback loop. Accordingly, pS473-TRIM28 promotes CRPC progression, which is mitigated by RSK inhibition. In summary, our study reveals a critical role of the RSK1-TRIM28-E2F1 axis in CRPC progression, which may be exploited as a vulnerability in treating Rb-deficient CRPC.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295966","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}

引用次数: 0