JCI insight最新文献_第10页

Peripherally restricted PICK1 inhibitor mPD5 ameliorates pain behaviors in murine inflammatory and neuropathic pain models. 外周限制性 PICK1 抑制剂 mPD5 可改善小鼠炎症性和神经性疼痛模型中的疼痛行为。

IF 8 1区医学

JCI insight Pub Date : 2024-09-17 DOI: 10.1172/jci.insight.170976

Kathrine Louise Jensen,Nikolaj Riis Christensen,Carolyn Marie Goddard,Sara Elgaard Jager,Gith Noes-Holt,Ida Buur Kanneworff,Alexander Jakobsen,Lucía Jiménez-Fernández,Emily G Peck,Line Sivertsen,Raquel Comaposada-Baro,Grace Anne Houser,Felix Paul Mayer,Marta Diaz-delCastillo,Marie Løth Topp,Chelsea Hopkins,Cecilie Dubgaard Thomsen,Ahmed Barakat Ibrahim Soltan,Federik Grønbæk Tidenmand,Lise Arleth,Anne-Marie Heegaard,Andreas Toft Sørensen,Kenneth Lindegaard Madsen

{"title":"Peripherally restricted PICK1 inhibitor mPD5 ameliorates pain behaviors in murine inflammatory and neuropathic pain models.","authors":"Kathrine Louise Jensen,Nikolaj Riis Christensen,Carolyn Marie Goddard,Sara Elgaard Jager,Gith Noes-Holt,Ida Buur Kanneworff,Alexander Jakobsen,Lucía Jiménez-Fernández,Emily G Peck,Line Sivertsen,Raquel Comaposada-Baro,Grace Anne Houser,Felix Paul Mayer,Marta Diaz-delCastillo,Marie Løth Topp,Chelsea Hopkins,Cecilie Dubgaard Thomsen,Ahmed Barakat Ibrahim Soltan,Federik Grønbæk Tidenmand,Lise Arleth,Anne-Marie Heegaard,Andreas Toft Sørensen,Kenneth Lindegaard Madsen","doi":"10.1172/jci.insight.170976","DOIUrl":"https://doi.org/10.1172/jci.insight.170976","url":null,"abstract":"Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting one in five adults. Current treatment is compromised by dose-limiting side effects including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we developed and characterized a cell-permeable fatty acid conjugated bivalent peptide inhibitor of PICK1 and assessed its effects on acute and chronic pain. The myristoylated myr-NPEG4-(HWLKV)2 (mPD5), self-assembled into core-shell micelles that provided favourable pharmacodynamic properties and relieved evoked mechanical and thermal hypersensitivity, as well as ongoing hypersensitivity, and anxio-depressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt side effects were associated with mPD5 administration, and it had no effect on acute nociception. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks post SNI surgery) and while the effect of a single injection ceased after a few hours, repeated administration provided pain relief lasting up to 20 hours after the last injection.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263854","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

CREB-binding protein/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in triple-negative breast cancer. 抑制 CREB 结合蛋白/P300 溴链可减少中性粒细胞的聚集，激活三阴性乳腺癌的抗肿瘤免疫。

IF 8 1区医学

JCI insight Pub Date : 2024-09-17 DOI: 10.1172/jci.insight.182621

Xueying Yuan,Xiaoxin Hao,Hilda L Chan,Na Zhao,Diego A Pedroza,Fengshuo Liu,Kang Le,Alex J Smith,Sebastian J Calderon,Nadia Lieu,Michael J Soth,Philip Jones,Xiang H-F Zhang,Jeffrey M Rosen

{"title":"CREB-binding protein/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in triple-negative breast cancer.","authors":"Xueying Yuan,Xiaoxin Hao,Hilda L Chan,Na Zhao,Diego A Pedroza,Fengshuo Liu,Kang Le,Alex J Smith,Sebastian J Calderon,Nadia Lieu,Michael J Soth,Philip Jones,Xiang H-F Zhang,Jeffrey M Rosen","doi":"10.1172/jci.insight.182621","DOIUrl":"https://doi.org/10.1172/jci.insight.182621","url":null,"abstract":"Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated cytotoxic T cells. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263856","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

Characterization of SMA Type II Skeletal Muscle from Treated Patients shows Mitochondrial Deficiency and Denervation. 治疗过的 SMA II 型骨骼肌患者的特征显示线粒体缺乏和去神经化。

IF 8 1区医学

JCI insight Pub Date : 2024-09-12 DOI: 10.1172/jci.insight.180992

Fiorella Grandi,Stéphanie Astord,Sonia Pezet,Elèna Gidaja,Sabrina Mazzucchi,Maud Chapart,Stéphane Vasseur,Kamel Mamchaoui,Piera Smeriglio

{"title":"Characterization of SMA Type II Skeletal Muscle from Treated Patients shows Mitochondrial Deficiency and Denervation.","authors":"Fiorella Grandi,Stéphanie Astord,Sonia Pezet,Elèna Gidaja,Sabrina Mazzucchi,Maud Chapart,Stéphane Vasseur,Kamel Mamchaoui,Piera Smeriglio","doi":"10.1172/jci.insight.180992","DOIUrl":"https://doi.org/10.1172/jci.insight.180992","url":null,"abstract":"Spinal muscular atrophy (SMA) is a recessive, developmental disorder caused by the genetic loss or mutation of the gene SMN1 (Survival of Motor Neuron 1). SMA is characterized by neuromuscular symptoms and muscle weakness. Several years ago, SMA treatment underwent a radical transformation, with the approval of three different SMN-dependent disease modifying therapies. This includes two SMN2 splicing therapies - Risdiplam and Nusinersen. One main challenge for Type II SMA patients treated with these drugs is ongoing muscle fatigue, limited mobility, and other skeletal problems. To date, few molecular studies have been conducted on SMA-patient derived tissues after treatment, limiting our understanding of what targets remain after the principal spinal cord targeted therapies are applied. Therefore, we collected paravertebral muscle from eight Type II patients undergoing spinal surgery for scoliosis and seven controls. We used RNA-sequencing to characterize their transcriptional profiles and correlate these with muscle histology. Despite the limited cohort size and heterogeneity, we observed a consistent loss of oxidative phosphorylation machinery of the mitochondria, a decrease in mitochondrial DNA copy number, and a correlation between signals of cellular stress, denervation and increased fibrosis. This work provides new putative targets for combination therapies for Type II SMA.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263855","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

Targeted long-read sequencing enriches disease-relevant genomic regions of interest to provide complete Mendelian disease diagnostics. 靶向长线程测序能富集与疾病相关的基因组感兴趣区，提供完整的孟德尔疾病诊断。

IF 8 1区医学

JCI insight Pub Date : 2024-09-12 DOI: 10.1172/jci.insight.183902

Kenji Nakamichi,Jennifer Huey,Riccardo Sangermano,Emily M Place,Kinga M Bujakowska,Molly Marra,Lesley A Everett,Paul Yang,Jennifer R Chao,Russell N Van Gelder,Debarshi Mustafi

{"title":"Targeted long-read sequencing enriches disease-relevant genomic regions of interest to provide complete Mendelian disease diagnostics.","authors":"Kenji Nakamichi,Jennifer Huey,Riccardo Sangermano,Emily M Place,Kinga M Bujakowska,Molly Marra,Lesley A Everett,Paul Yang,Jennifer R Chao,Russell N Van Gelder,Debarshi Mustafi","doi":"10.1172/jci.insight.183902","DOIUrl":"https://doi.org/10.1172/jci.insight.183902","url":null,"abstract":"Despite advances in sequencing technologies, a molecular diagnosis remains elusive in many Mendelian disease patients. Current short-read clinical sequencing approaches cannot provide chromosomal phase information or epigenetic information without further sample processing, which is not routinely done and can result in an incomplete molecular diagnosis in patients. The ability to provide phased genetic and epigenetic information from a single sequencing run would improve the diagnostic rate of Mendelian conditions. Here we describe Targeted Long-read Sequencing of Mendelian Disease genes (TaLon-SeqMD) using a real-time adaptive sequencing approach. Optimization of bioinformatic targeting enabled selective enrichment of multiple disease-causing regions of the human genome. Haplotype-resolved variant calling and simultaneous resolution of epigenetic base modification could be achieved in a single sequencing run. The TaLon-SeqMD approach was validated in a cohort of 18 subjects with previous genetic testing targeting 373 inherited retinal disease (IRD) genes, yielding the complete molecular diagnosis in each case. This approach was then applied in two IRD cases with inconclusive testing, which uncovered non-coding and structural variants that were difficult to characterize by standard short-read sequencing. Overall, these results demonstrate TaLon-SeqMD as an approach to provide rapid phased-variant calling to provide the molecular basis of Mendelian diseases.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263857","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

A positive cytokine/chemokine feedback loop establishes plasmacytoid dendritic cell-driven autoimmune pancreatitis in IgG4-related disease. 细胞因子/趋化因子正反馈环路在 IgG4 相关疾病中建立了浆细胞树突状细胞驱动的自身免疫性胰腺炎。

IF 8 1区医学

JCI insight Pub Date : 2024-09-12 DOI: 10.1172/jci.insight.167910

Akane Hara,Tomohiro Watanabe,Kosuke Minaga,Tomoe Yoshikawa,Masayuki Kurimoto,Ikue Sekai,Yasuhiro Masuta,Ryutaro Takada,Yasuo Otsuka,Ken Kamata,Shiki Takamura,Masatoshi Kudo,Warren Strober

{"title":"A positive cytokine/chemokine feedback loop establishes plasmacytoid dendritic cell-driven autoimmune pancreatitis in IgG4-related disease.","authors":"Akane Hara,Tomohiro Watanabe,Kosuke Minaga,Tomoe Yoshikawa,Masayuki Kurimoto,Ikue Sekai,Yasuhiro Masuta,Ryutaro Takada,Yasuo Otsuka,Ken Kamata,Shiki Takamura,Masatoshi Kudo,Warren Strober","doi":"10.1172/jci.insight.167910","DOIUrl":"https://doi.org/10.1172/jci.insight.167910","url":null,"abstract":"The pathogenesis of the murine model of autoimmune pancreatitis associated with IgG4-related disease (AIP/IgG4-RD) induced by administration of polyinosinic-polycytidylic acid, is incompletely understood. While it is known that murine and human AIP/IgG4-RD is driven by plasmacytoid dendritic cells (pDCs) producing IFN-α, the origin of these cells and their relation to effector T cells is not known. Here we show that murine AIP was initiated by TLR3-bearing conventional DCs in the uninflamed pancreas whose activation by TLR3 ligand (polyinosinic-polycytidylic acid) caused IFN-α, CXCL9, and CXCL10 secretion. This, in turn, induced pancreatic recruitment of CXCR3+ T cells and these T cells, via their secretion of CCL25, facilitated migration of pDCs bearing CCR9 into the pancreas. This established a feedback loop anchored by the now dominant pDC production of IFN-α and the continued CXCR3+ T cell facilitation of pDC migration. Remarkably, the interaction between CXCR3+ T cells and pDCs also existed at the functional levels since this interaction enhanced the production of CCL25 and IFN-α by CXCR3+ T cells and pDCs, respectively. Evidence presented here that a similar disease mechanism was present in human AIP/IgG4-RD creates new avenues of disease treatment.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263974","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

Missense variants in CMS22 patients reveal that PREPL has both enzymatic and nonenzymatic functions. CMS22 患者的错义变体显示，PREPL 具有酶和非酶功能。

IF 6.3 1区医学

JCI insight Pub Date : 2024-09-10 DOI: 10.1172/jci.insight.179276

Yenthe Monnens, Anastasia Theodoropoulou, Karen Rosier, Kritika Bhalla, Alexia Mahy, Roeland Vanhoutte, Sandra Meulemans, Edoardo Cavani, Aleksandar Antanasijevic, Irma Lemmens, Jennifer A Lee, Catherine J Spellicy, Richard J Schroer, Ricardo A Maselli, Chamindra G Laverty, Patrizia Agostinis, David J Pagliarini, Steven Verhelst, Maria J Marcaida, Anne Rochtus, Matteo Dal Peraro, John Wm Creemers

{"title":"Missense variants in CMS22 patients reveal that PREPL has both enzymatic and nonenzymatic functions.","authors":"Yenthe Monnens, Anastasia Theodoropoulou, Karen Rosier, Kritika Bhalla, Alexia Mahy, Roeland Vanhoutte, Sandra Meulemans, Edoardo Cavani, Aleksandar Antanasijevic, Irma Lemmens, Jennifer A Lee, Catherine J Spellicy, Richard J Schroer, Ricardo A Maselli, Chamindra G Laverty, Patrizia Agostinis, David J Pagliarini, Steven Verhelst, Maria J Marcaida, Anne Rochtus, Matteo Dal Peraro, John Wm Creemers","doi":"10.1172/jci.insight.179276","DOIUrl":"10.1172/jci.insight.179276","url":null,"abstract":"Congenital myasthenic syndrome-22 (CMS22, OMIM 616224) is a rare genetic disorder caused by deleterious genetic variation in the prolyl endopeptidase-like (PREPL) gene. Previous reports have described patients with deletions and nonsense variants in PREPL, but nothing is known about the effect of missense variants in the pathology of CMS22. In this study, we have functionally characterized missense variants in PREPL from 3 patients with CMS22, all with hallmark phenotypes. Biochemical evaluation revealed that these missense variants do not impair hydrolase activity, thereby challenging the conventional diagnostic criteria and disease mechanism. Structural analysis showed that the variants affect regions most likely involved in intraprotein or protein-protein interactions. Indeed, binding to a selected group of known interactors was differentially reduced for the 3 variants. The importance of nonhydrolytic functions of PREPL was investigated in catalytically inactive PREPL p.Ser559Ala cell lines, which showed that hydrolytic activity of PREPL is needed for normal mitochondrial function but not for regulating AP1-mediated transport in the transgolgi network. In conclusion, these studies showed that CMS22 can be caused not only by deletion and truncation of PREPL but also by missense variants that do not necessarily result in a loss of hydrolytic activity of PREPL.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11385081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855597","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

Staphylococcus aureus exacerbates dermal IL-33/ILC2 axis activation through evoking RIPK3/MLKL-mediated necroptosis of dry skin. 金黄色葡萄球菌通过唤起 RIPK3/MLKL 介导的干燥皮肤坏死，加剧了皮肤 IL-33/ILC2 轴的激活。

IF 6.3 1区医学

JCI insight Pub Date : 2024-09-10 DOI: 10.1172/jci.insight.185878

Chia-Hui Luo, Alan Chuan-Ying Lai, Chun-Chou Tsai, Wei-Yu Chen, Yu-Shan Chang, Ethan Ja-Chen Chung, Ya-Jen Chang

引用次数: 0

Go, Flight. 开始，飞行

IF 6.3 1区医学

JCI insight Pub Date : 2024-09-10 DOI: 10.1172/jci.insight.185748

Oliver Eickelberg

引用次数: 0

EGR2 is an epigenomic regulator of phagocytosis and antifungal immunity in alveolar macrophages. EGR2 是肺泡巨噬细胞吞噬和抗真菌免疫的表观基因组调控因子。

IF 6.3 1区医学

JCI insight Pub Date : 2024-09-10 DOI: 10.1172/jci.insight.164009

Zsuzsanna Kolostyak, Dora Bojcsuk, Viktoria Baksa, Zsuzsa Mathene Szigeti, Krisztian Bene, Zsolt Czimmerer, Pal Boto, Lina Fadel, Szilard Poliska, Laszlo Halasz, Petros Tzerpos, Wilhelm K Berger, Andres Villabona-Rueda, Zsofia Varga, Tunde Kovacs, Andreas Patsalos, Attila Pap, Gyorgy Vamosi, Peter Bai, Balazs Dezso, Matthew Spite, Franco R D'Alessio, Istvan Szatmari, Laszlo Nagy

{"title":"EGR2 is an epigenomic regulator of phagocytosis and antifungal immunity in alveolar macrophages.","authors":"Zsuzsanna Kolostyak, Dora Bojcsuk, Viktoria Baksa, Zsuzsa Mathene Szigeti, Krisztian Bene, Zsolt Czimmerer, Pal Boto, Lina Fadel, Szilard Poliska, Laszlo Halasz, Petros Tzerpos, Wilhelm K Berger, Andres Villabona-Rueda, Zsofia Varga, Tunde Kovacs, Andreas Patsalos, Attila Pap, Gyorgy Vamosi, Peter Bai, Balazs Dezso, Matthew Spite, Franco R D'Alessio, Istvan Szatmari, Laszlo Nagy","doi":"10.1172/jci.insight.164009","DOIUrl":"10.1172/jci.insight.164009","url":null,"abstract":"Alveolar macrophages (AMs) act as gatekeepers of the lung's immune responses, serving essential roles in recognizing and eliminating pathogens. The transcription factor (TF) early growth response 2 (EGR2) has been recently described as required for mature AMs in mice; however, its mechanisms of action have not been explored. Here, we identified EGR2 as an epigenomic regulator and likely direct proximal transcriptional activator in AMs using epigenomic approaches (RNA sequencing, ATAC sequencing, and CUT&RUN). The predicted direct proximal targets of EGR2 included a subset of AM identity genes and ones related to pathogen recognition, phagosome maturation, and adhesion, such as Clec7a, Atp6v0d2, Itgb2, Rhoc, and Tmsb10. We provided evidence that EGR2 deficiency led to impaired zymosan internalization and reduced the capacity to respond to Aspergillus fumigatus. Mechanistically, the lack of EGR2 altered the transcriptional response, secreted cytokines (i.e., CXCL11), and inflammation-resolving lipid mediators (i.e., RvE1) of AMs during in vivo zymosan-induced inflammation, which manifested in impaired resolution. Our findings demonstrated that EGR2 is a key proximal transcriptional activator and epigenomic bookmark in AMs responsible for select, distinct components of cell identity and a protective transcriptional and epigenomic program against fungi.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11385099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751702","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

HIV-1 latency reversal and immune enhancing activity of IL-15 is not influenced by sex hormones. IL-15的HIV-1潜伏逆转和免疫增强活性不受性激素影响。

IF 6.3 1区医学

JCI insight Pub Date : 2024-09-10 DOI: 10.1172/jci.insight.180609

Carissa S Holmberg, Callie Levinger, Marie Abongwa, Cristina Ceriani, Nancie M Archin, Marc Siegel, Mimi Ghosh, Alberto Bosque

{"title":"HIV-1 latency reversal and immune enhancing activity of IL-15 is not influenced by sex hormones.","authors":"Carissa S Holmberg, Callie Levinger, Marie Abongwa, Cristina Ceriani, Nancie M Archin, Marc Siegel, Mimi Ghosh, Alberto Bosque","doi":"10.1172/jci.insight.180609","DOIUrl":"10.1172/jci.insight.180609","url":null,"abstract":"The role of different biological variables including biological sex, age, and sex hormones in Human immunodeficiency virus (HIV) cure approaches is not well understood. The γc-cytokine IL-15 is a clinically relevant cytokine that promotes immune activation and mediates HIV reactivation from latency. In this work, we examined the interplay that biological sex, age, and sex hormones 17β-estradiol, progesterone, and testosterone may have on the biological activity of IL-15. We found that IL-15-mediated CD4+ T cell activation was higher in female donors than in male donors. This difference was abrogated at high 17β-estradiol concentration. Additionally, there was a positive correlation between age and both IL-15-mediated CD8+ T cell activation and IFN-γ production. In a primary cell model of latency, biological sex, age, or sex hormones did not influence the ability of IL-15 to reactivate latent HIV. Finally, 17β-estradiol did not consistently affect reactivation of translation-competent reservoirs in CD4+ T cells from people living with HIV who are antiretroviral therapy (ART) suppressed. Our study has found that biological sex and age, but not sex hormones, may influence some of the biological activities of IL-15. Understanding how different biological variables may affect HIV cure therapies will help us evaluate current and future clinical trials aimed toward HIV cure in diverse populations.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11389825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855596","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