IF 6.3 1区医学

JCI insight Pub Date : 2024-11-19 DOI: 10.1172/jci.insight.184545

David A Schoenfeld, Dijana Djureinovic, David G Su, Lin Zhang, Benjamin Y Lu, Larisa Kamga, Jacqueline E Mann, John D Huck, Michael Hurwitz, David A Braun, Lucia Jilaveanu, Aaron M Ring, Harriet M Kluger

{"title":"Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti-CTLA-4 in renal cell carcinoma.","authors":"David A Schoenfeld, Dijana Djureinovic, David G Su, Lin Zhang, Benjamin Y Lu, Larisa Kamga, Jacqueline E Mann, John D Huck, Michael Hurwitz, David A Braun, Lucia Jilaveanu, Aaron M Ring, Harriet M Kluger","doi":"10.1172/jci.insight.184545","DOIUrl":"10.1172/jci.insight.184545","url":null,"abstract":"The cytokine interleukin-18 (IL-18) has immunostimulatory effects but is negatively regulated by a secreted binding protein, IL-18BP, that limits IL-18's anti-cancer efficacy. A \"decoy-resistant\" form of IL-18 (DR-18), that avoids sequestration by IL-18BP while maintaining its immunostimulatory potential, has recently been developed. Here, we investigated the therapeutic potential of DR-18 in renal cell carcinoma (RCC). Using pan-tumor transcriptomic data, we found that clear cell RCC had among the highest expression of IL-18 receptor subunits and IL18BP of tumor types in the database. In samples from RCC patients treated with immune checkpoint inhibitors, IL-18BP protein expression increased in the tumor microenvironment and circulating in plasma in non-responding patients and decreased in the majority of responding patients. We used immunocompetent RCC murine models to assess the efficacy of DR-18 in combination with single- and dual-agent anti-PD-1 and anti-CTLA-4. In contrast to preclinical models of other tumor types, in RCC models DR-18 enhanced the activity of anti-CTLA-4 but not anti-PD-1 treatment. This activity correlated with intra-tumoral enrichment and clonal expansion of effector CD8+ T cells, decreased regulatory T cell levels, and enrichment of pro-inflammatory, anti-tumor myeloid cell populations. Our findings support further clinical investigation of the combination of DR-18 and anti-CTLA-4 in RCC.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667497","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

β-catenin disruption decreases macrophage exosomal α-SNAP and impedes Treg differentiation in acute liver injury. β-catenin干扰会减少巨噬细胞外泌体α-SNAP，阻碍急性肝损伤中Treg的分化。

IF 6.3 1区医学

JCI insight Pub Date : 2024-11-19 DOI: 10.1172/jci.insight.182515

Ruobin Zong, Yujie Liu, Mengya Zhang, Buwei Liu, Wei Zhang, Hankun Hu, Changyong Li

{"title":"β-catenin disruption decreases macrophage exosomal α-SNAP and impedes Treg differentiation in acute liver injury.","authors":"Ruobin Zong, Yujie Liu, Mengya Zhang, Buwei Liu, Wei Zhang, Hankun Hu, Changyong Li","doi":"10.1172/jci.insight.182515","DOIUrl":"10.1172/jci.insight.182515","url":null,"abstract":"Hepatic macrophages and regulatory T cells (Tregs) play an important role in the maintenance of liver immune homeostasis, but the mechanism by which hepatic macrophages regulate Tregs in acute liver injury remains largely unknown. Here, we found that the hepatic Treg proportion and β-catenin expression in hepatic macrophages were associated with acetaminophen (APAP) and D-galactosamine (D-GalN)/ lipopolysaccharide (LPS)-induced acute liver injury. Interestingly, β-catenin was markedly upregulated only in infiltrating macrophages, but not in resident Kupffer cells. Myeloid-specific β-catenin knockout mice showed an increased inflammatory cell infiltration and hepatocyte apoptosis. Moreover, myeloid β-catenin deficiency decreased the hepatic Treg proportion in the injured liver. Mechanistically, in vitro co-culture experiments revealed that macrophage β-catenin modulated its exosome composition, and influenced Treg differentiation. Using mass spectrometry-based proteomics, we identified that macrophage β-catenin activation increased the level of exosomal α-SNAP, which in turn promoted Treg differentiation. Overall, our findings demonstrated a molecular mechanism that macrophage β-catenin regulated the Treg proportion in the liver by enhancing the expression of exosomal α-SNAP, providing insights into the pathophysiology of acute liver injury.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667504","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

NDR2 is critical for the osteoclastogenesis by regulating ULK1-mediated mitophagy. NDR2 通过调节 ULK1 介导的有丝分裂，对破骨细胞的形成至关重要。

IF 6.3 1区医学

JCI insight Pub Date : 2024-11-19 DOI: 10.1172/jci.insight.180409

Xiangxi Kong, Zhi Shan, Yihao Zhao, Siyue Tao, Jingyun Chen, Zhongyin Ji, Jiayan Jin, Junhui Liu, Wenlong Lin, Xiaojian Wang, Jian Wang, Fengdong Zhao, Bao Huang, Jian Chen

{"title":"NDR2 is critical for the osteoclastogenesis by regulating ULK1-mediated mitophagy.","authors":"Xiangxi Kong, Zhi Shan, Yihao Zhao, Siyue Tao, Jingyun Chen, Zhongyin Ji, Jiayan Jin, Junhui Liu, Wenlong Lin, Xiaojian Wang, Jian Wang, Fengdong Zhao, Bao Huang, Jian Chen","doi":"10.1172/jci.insight.180409","DOIUrl":"10.1172/jci.insight.180409","url":null,"abstract":"Bone homeostasis primarily stems from the balance between osteoblasts and osteoclasts, wherein an augmented number or heightened activity of osteoclasts is a prevalent etiological factor in the development of bone loss. Nuclear Dbf2-related kinase (NDR2), also known as STK38L, is a member of the Hippo family with serine/threonine kinase activity. We unveiled an upregulation of NDR2 expression during osteoclast differentiation. Manipulation of NDR2 levels through knockdown or overexpression facilitated or hindered osteoclast differentiation respectively, indicating a negative feedback role for NDR2 in the osteoclastogenesis. Myeloid NDR2-dificient mice (Lysm+NDR2f/f) showed lower bone mass and further exacerbated ovariectomy-induced or aging-related bone loss. Mechanically, NDR2 enhanced autophagy and mitophagy through mediating ULK1 instability. In addition, ULK1 inhibitor (ULK1-IN2) ameliorated NDR2 cKO-induced bone loss. Finally, we clarified a significant inverse association between NDR2 expression and the occurrence of osteoporosis in patients. In a word, NDR2-ULK1-mitophagy axis was a potential innovative therapeutic target for the prevention and management of bone loss.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667501","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

Mutation of CRYAB encoding a conserved mitochondrial chaperone and anti-apoptotic protein causes hereditary optic atrophy. 编码线粒体伴侣蛋白和抗凋亡蛋白的 CRYAB 基因突变会导致遗传性视神经萎缩。

IF 6.3 1区医学

JCI insight Pub Date : 2024-11-19 DOI: 10.1172/jci.insight.182209

Chenghui Wang, Liyao Zhang, Zhipeng Nie, Min Liang, Hanqing Liu, Qiuzi Yi, Chunyan Wang, Cheng Ai, Juanjuan Zhang, Yinglong Gao, Yanchun Ji, Min-Xin Guan

{"title":"Mutation of CRYAB encoding a conserved mitochondrial chaperone and anti-apoptotic protein causes hereditary optic atrophy.","authors":"Chenghui Wang, Liyao Zhang, Zhipeng Nie, Min Liang, Hanqing Liu, Qiuzi Yi, Chunyan Wang, Cheng Ai, Juanjuan Zhang, Yinglong Gao, Yanchun Ji, Min-Xin Guan","doi":"10.1172/jci.insight.182209","DOIUrl":"10.1172/jci.insight.182209","url":null,"abstract":"The degeneration of retinal ganglion cells (RGC) due to mitochondrial dysfunctions manifests optic neuropathy. However, the molecular components of RGC linked to optic neuropathy manifestations remain largely unknown. Here, we identified a novel optic atrophy-causative CRYAB gene encoding a highly conserved major lens protein acting as mitochondrial chaperone and possessing anti-apoptotic activities. The heterozygous CRYAB mutation (c.313G>A, p. Glu105Lys) was cosegregated with autosomal dominant inheritance of optic atrophy in 3 Chinese families. The p.E105K mutation altered the structure and function of CRYAB, including decreased stability, reduced formation of oligomers and decreasing chaperone activity. Coimmunoprecipitation indicated that the p.E105K mutation reduced the interaction of CRYAB with apoptosis-associated cytochrome c and VDAC. The cell lines carrying the p.E105K mutation displayed promoting apoptosis, defective assembly, stability and activities of oxidative phosphorylation system and imbalance of mitochondrial dynamics. Involvement of CRYAB in optic atrophy was confirmed by phenotypic evaluations of Cryabp.E105K knock-in mice. These mutant mice exhibited ocular lesions including changing intra-retina layers, degeneration of RGCs, photoreceptor deficits and abnormal retinal vasculature. Furthermore, Cryab-deficient mice displayed elevated apoptosis and mitochondrial dysfunctions. Our findings provide new insight of pathophysiology of optic atrophy arising from RGC degeneration caused by CRYAB deficiency-induced elevated apoptosis and mitochondrial dysfunctions.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667500","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

Aiolos promotes CXCR3 expression on TH1 cells via positive regulation of IFNγ/STAT1 signaling. Aiolos 通过正向调节 IFNγ/STAT1 信号，促进 TH1 细胞中 CXCR3 的表达。

IF 6.3 1区医学

JCI insight Pub Date : 2024-11-19 DOI: 10.1172/jci.insight.180287

Melissa R Leonard, Devin M Jones, Kaitlin A Read, Srijana Pokhrel, Jasmine A Tuazon, Robert T Warren, Jacob S Yount, Kenneth J Oestreich

{"title":"Aiolos promotes CXCR3 expression on TH1 cells via positive regulation of IFNγ/STAT1 signaling.","authors":"Melissa R Leonard, Devin M Jones, Kaitlin A Read, Srijana Pokhrel, Jasmine A Tuazon, Robert T Warren, Jacob S Yount, Kenneth J Oestreich","doi":"10.1172/jci.insight.180287","DOIUrl":"10.1172/jci.insight.180287","url":null,"abstract":"CD4+ T helper 1 (TH1) cells coordinate adaptive immune responses to intracellular pathogens, including viruses. Key to this function is the ability of TH1 cells to migrate within secondary lymphoid tissues, as well as to sites of inflammation, which relies on signals received through the chemokine receptor CXCR3. CXCR3 expression is driven by the TH1 lineage-defining transcription factor T-bet, and the cytokine-responsive Signal Transducer and Activator of Transcription (STAT) family members STAT1 and STAT4. Here, we identify the Ikaros zinc finger (IkZF) transcription factor Aiolos (Ikzf3) as an additional positive regulator of CXCR3 both in vitro and in vivo using a murine model of influenza virus infection. Mechanistically, we find that Aiolos-deficient CD4+ T cells exhibit decreased expression of key components of the IFNγ/STAT1 signaling pathway, including JAK2 and STAT1. Consequently, Aiolos deficiency results in decreased levels of STAT1 tyrosine phosphorylation and reduced STAT1 enrichment at the Cxcr3 promoter. We further find that Aiolos and STAT1 form a positive feedback loop via reciprocal regulation of each other downstream of IFNγ signaling. Collectively, our study demonstrates that Aiolos promotes CXCR3 expression on TH1 cells by propagating the IFNγ/STAT1 cytokine signaling pathway.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667494","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

Recurrent Small Variants in NESP55/NESPAS Associated with Broad GNAS Methylation Defects and Pseudohypoparathyroidism Type 1b. NESP55/NESPAS中的复发性小变异与广泛的GNAS甲基化缺陷和假性甲状旁腺功能减退症1b型有关

IF 6.3 1区医学

JCI insight Pub Date : 2024-11-14 DOI: 10.1172/jci.insight.185874

Dong Li, Suzanne Jan de Beur, Cuiping Hou, Maura Rz Ruzhnikov, Hilary Seeley, Garry R Cutting, Molly B Sheridan, Michael A Levine

{"title":"Recurrent Small Variants in NESP55/NESPAS Associated with Broad GNAS Methylation Defects and Pseudohypoparathyroidism Type 1b.","authors":"Dong Li, Suzanne Jan de Beur, Cuiping Hou, Maura Rz Ruzhnikov, Hilary Seeley, Garry R Cutting, Molly B Sheridan, Michael A Levine","doi":"10.1172/jci.insight.185874","DOIUrl":"https://doi.org/10.1172/jci.insight.185874","url":null,"abstract":"Pseudohypoparathyroidism type 1B (PHP1B) is associated with epigenetic changes on the maternal allele of the imprinted GNAS gene that inhibit expression of the alpha subunit of Gs (Gsα), thereby leading to parathyroid hormone resistance in renal proximal tubule cells where expression of Gs from the paternal GNAS allele is normally silent. Although all patients with PHP1B show loss of methylation for the exon A/B differentially methylated region (DMR), some patients with autosomal dominant PHP1B (AD-PHP1B) and most patients with sporadic PHP1B have additional methylation defects that affect the DMRs corresponding to exons XL, AS1, and NESP. Because the genetic defect is unknown in most of these patients, we sought to identify the underlying genetic basis for AD-PHP1B in two multigenerational families with broad GNAS methylation defects and negative clinical exomes. Genome sequencing identified small GNAS variants in each family that were also present in unrelated PHP1B subjects in a replication cohort. Maternal transmission of one GNAS microdeletion showed reduced penetrance in some unaffected patients. Expression of AS transcripts was increased, and NESP was decreased, in cells from affected patients. These results suggest that the small deletion activate AS transcription leading to methylation of the NESP DMR with consequent inhibition of NESP transcription, and thereby provide a potential mechanism for PHP1B.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620661","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

Insulin mitigates acute ischemia induced atrial fibrillation and sinoatrial node dysfunction ex vivo. 胰岛素可减轻急性缺血诱发的体内心房颤动和中房结节功能障碍。

IF 6.3 1区医学

JCI insight Pub Date : 2024-11-14 DOI: 10.1172/jci.insight.185961

Huiliang Qiu, Fan Li, Hannah Prachyl, Alejandra Patino-Guerrero, Michael Rubart, Wuqiang Zhu

{"title":"Insulin mitigates acute ischemia induced atrial fibrillation and sinoatrial node dysfunction ex vivo.","authors":"Huiliang Qiu, Fan Li, Hannah Prachyl, Alejandra Patino-Guerrero, Michael Rubart, Wuqiang Zhu","doi":"10.1172/jci.insight.185961","DOIUrl":"10.1172/jci.insight.185961","url":null,"abstract":"Acute atrial ischemia is a well-known cause of postoperative atrial fibrillation (POAF). However, mechanisms through which ischemia contributes to the development of POAF are not well understood. In this study, ex vivo Langendorff perfusion was used to induce acute ischemia and reperfusion in the heart in order to mimic POAF. Inducibility of atrial fibrillation (AF) was evaluated using programmed electrical stimulation and confirmed with open-atrium optical mapping. Compared to the control group without ischemia, 25 minutes of ischemia substantially increased the incidence of AF. The right atrium was more susceptible to AF than the left atrium. Administering insulin for 30 minutes before ischemia and during reperfusion with 25 minutes of ischemia greatly reduced the vulnerability to AF. However, insulin treatment during reperfusion only did not show substantial benefits against AF. Optical mapping studies showed that insulin mitigates ischemia-induced abnormal electrophysiology, including shortened action potential duration and effective refractory period, slowed conduction velocity, increased conduction heterogeneity, and altered calcium transients. In conclusion, insulin reduced the risk of acute ischemia/reperfusion-induced AF via improving the electrophysiology and calcium handling of atrial cardiomyocytes, which provides a potential therapy for POAF.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620638","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

High-resolution multimodal profiling of human epileptic brain activity via explanted depth electrodes. 通过植入的深度电极对人类癫痫脑部活动进行高分辨率多模态分析。

IF 6.3 1区医学

JCI insight Pub Date : 2024-11-14 DOI: 10.1172/jci.insight.184518

Anuj Kumar Dwivedi, Arun Mahesh, Albert Sanfeliu, Julian Larkin, Rebecca A Siwicki, Kieron J Sweeney, Donncha F O'Brien, Peter Widdess-Walsh, Simone Picelli, David C Henshall, Vijay K Tiwari

{"title":"High-resolution multimodal profiling of human epileptic brain activity via explanted depth electrodes.","authors":"Anuj Kumar Dwivedi, Arun Mahesh, Albert Sanfeliu, Julian Larkin, Rebecca A Siwicki, Kieron J Sweeney, Donncha F O'Brien, Peter Widdess-Walsh, Simone Picelli, David C Henshall, Vijay K Tiwari","doi":"10.1172/jci.insight.184518","DOIUrl":"https://doi.org/10.1172/jci.insight.184518","url":null,"abstract":"The availability and integration of electrophysiological and molecular data from the living brain is critical to understand and diagnose complex human disease. Intracranial stereo electroencephalography (SEEG) electrodes used for identifying the seizure focus on epilepsy patients could enable the integration of such multimodal data. Here, we report MoPEDE (Multimodal Profiling of Epileptic Brain Activity via Explanted Depth Electrodes), a method that recovers extensive protein-coding transcripts, including cell-type markers, DNA methylation and short variant profiles from explanted SEEG electrodes matched with electrophysiological and radiological data allowing for high-resolution reconstructions of brain structure and function. We find gene expression gradients that correspond with the neurophysiology-assigned epileptogenicity index but also outlier molecular fingerprints in some electrodes, potentially indicating seizure generation or propagation zones not detected during electroclinical assessments. Additionally, we identify DNA methylation profiles indicative of transcriptionally permissive or restrictive chromatin states and SEEG-adherent differentially expressed and methylated genes not previously associated with epilepsy. Together, these findings validate that RNA profiles and genome-wide epigenetic data from explanted SEEG electrodes offer high-resolution surrogate molecular landscapes of brain activity. The MoPEDE approach has the potential to enhance diagnostic decisions and deepen our understanding of epileptogenic network processes in the human brain.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620618","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

Profound reduction of HIV-1 reservoir cells over three decades of antiretroviral therapy started in early infancy. 经过 30 年的抗逆转录病毒治疗，HIV-1 储库细胞的大幅减少始于婴儿期。

IF 6.3 1区医学

JCI insight Pub Date : 2024-11-14 DOI: 10.1172/jci.insight.186550

Liliana C Vela, Leah Carrere, Chloe Naasz, Sruthi Kalavacherla, Toong Seng Tan, Lesley de Armas, Ce Gao, Xu G Yu, Savita G Pahwa, Katherine Luzuriaga, Mathias Lichterfeld

{"title":"Profound reduction of HIV-1 reservoir cells over three decades of antiretroviral therapy started in early infancy.","authors":"Liliana C Vela, Leah Carrere, Chloe Naasz, Sruthi Kalavacherla, Toong Seng Tan, Lesley de Armas, Ce Gao, Xu G Yu, Savita G Pahwa, Katherine Luzuriaga, Mathias Lichterfeld","doi":"10.1172/jci.insight.186550","DOIUrl":"https://doi.org/10.1172/jci.insight.186550","url":null,"abstract":"HIV-1 reservoir cells persist indefinitely during suppressive antiretroviral therapy (ART) in individuals who acquire infection in adulthood, but little is known about the longitudinal evolution of viral reservoir cells during long-term ART started during early infancy. We studied two fraternal twins who acquired HIV-1 perinatally, started ART at week 10 after birth and remained on ART for 28 years. We observed that the frequency of genome intact proviruses, determined by single-genome near full-length proviral sequencing, declined by approximately 4,000- to 13,000-fold during this period, indicating enhanced decay rates of intact proviruses even after adjusting for dilution effects from somatic growth. Despite analyzing more than one billion PBMC after 28 years of ART in each participant, no intact proviruses were detected in one participant, and one intact provirus was isolated in the other. The longitudinal decline of defective proviruses in the two participants was more similar to proviral decay kinetics reported in individuals who started ART during adulthood; moreover, clonal sequence clusters were readily detectable for defective proviruses but not for intact proviruses after 28 years of ART in the two twins. Together, these data suggest decreased long-term stability and increased immunological vulnerability of intact proviruses during long-term ART started in early infancy.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620659","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

12-Lipoxygenase inhibition delays onset of autoimmune diabetes in human gene replacement mice. 12-脂氧合酶抑制剂可延长人类基因替代小鼠自身免疫性糖尿病的发病时间。

IF 6.3 1区医学

JCI insight Pub Date : 2024-11-12 DOI: 10.1172/jci.insight.185299

Titli Nargis, Charanya Muralidharan, Jacob R Enriquez, Jiayi E Wang, Kerim B Kaylan, Advaita Chakraborty, Sarida Pratuangtham, Kayla Figatner, Jennifer B Nelson, Sarah C May, Jerry L Nadler, Matthew B Boxer, David J Maloney, Sarah A Tersey, Raghavendra G Mirmira

{"title":"12-Lipoxygenase inhibition delays onset of autoimmune diabetes in human gene replacement mice.","authors":"Titli Nargis, Charanya Muralidharan, Jacob R Enriquez, Jiayi E Wang, Kerim B Kaylan, Advaita Chakraborty, Sarida Pratuangtham, Kayla Figatner, Jennifer B Nelson, Sarah C May, Jerry L Nadler, Matthew B Boxer, David J Maloney, Sarah A Tersey, Raghavendra G Mirmira","doi":"10.1172/jci.insight.185299","DOIUrl":"10.1172/jci.insight.185299","url":null,"abstract":"Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing beta cells and involves an interplay between beta cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in beta cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12 gene. Our finding demonstrated that VLX-1005, a potent 12-LOX inhibitor, effectively delayed the onset of autoimmune diabetes in human gene replacement non-obese diabetic mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages with accompanying increases in immune checkpoint molecule PD-L1, suggesting a shift towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets and polarized proinflammatory macrophages revealed significant alteration of cytokine-responsive pathways and a reduction in interferon response after VLX-1005 treatment. Our studies demonstrated that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620601","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

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