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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 Q1 MEDICINE, RESEARCH & EXPERIMENTAL 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
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.
慢性疼痛是一个复杂、使人衰弱且不断升级的全球性健康问题,影响着五分之一的成年人。目前的治疗方法受到剂量限制性副作用的影响,包括药物滥用、丧失社交和职业能力、疲劳、嗜睡和冷漠。PICK1 已成为治疗慢性疼痛的一个有希望的靶点。在这里,我们开发并鉴定了一种细胞渗透性脂肪酸共轭二价肽 PICK1 抑制剂,并评估了它对急性和慢性疼痛的影响。肉豆蔻酰化的 myr-NPEG4-(HWLKV)2 (mPD5) 可自组装成核壳胶束,具有良好的药效学特性,在神经病理性疼痛和炎症性疼痛小鼠模型中皮下注射后,可缓解诱发的机械和热超敏反应、持续超敏反应以及焦虑抑郁症状。给药 mPD5 没有明显的副作用,对急性痛觉也没有影响。最后,神经性疼痛在慢性阶段(SNI 手术后 18 周)也得到了缓解,虽然单次注射的效果在几小时后就会消失,但重复注射可使疼痛缓解在最后一次注射后持续长达 20 小时。
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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 Q1 MEDICINE, RESEARCH & EXPERIMENTAL 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
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.
肿瘤相关中性粒细胞(TANs)已被证明可促进免疫抑制和肿瘤进展,TANs的高频率可预测三阴性乳腺癌(TNBC)的不良预后。CREB 结合蛋白(CBP)/P300 功能失调已在多种癌症类型中被观察到。CBP/P300的溴结构域(BRD)被证明可调节其活性。在这项研究中,我们发现一种新型选择性 CBP/P300 BRD 抑制剂 IACS-70654 能减少 TANs 并抑制富含中性粒细胞的 TNBC 模型的生长。在骨髓中,CBP/P300 BRD抑制剂可减少肿瘤驱动的中性粒细胞祖细胞异常分化和增殖。抑制CBP/P300 BRD还能通过诱导肿瘤细胞的IFN反应和MHCI表达以及增加肿瘤浸润的细胞毒性T细胞来刺激免疫反应。此外,IACS-70654 还能改善富含中性粒细胞的 TNBC 模型对多西他赛和免疫检查点阻断的反应。这为在未来治疗富含中性粒细胞的TNBC的临床试验中将CBP/P300 BRD抑制剂与标准疗法相结合提供了理论依据。
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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 Q1 MEDICINE, RESEARCH & EXPERIMENTAL 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
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.
脊髓性肌萎缩症(SMA)是一种隐性发育障碍性疾病,由基因 SMN1(运动神经元存活 1)缺失或突变引起。SMA 的特征是神经肌肉症状和肌肉无力。几年前,随着三种不同的 SMN 依赖性疾病调节疗法获得批准,SMA 的治疗发生了根本性的转变。其中包括两种SMN2剪接疗法--Risdiplam和Nusinersen。接受这些药物治疗的 II 型 SMA 患者面临的一个主要挑战是持续的肌肉疲劳、活动受限和其他骨骼问题。迄今为止,很少有人对 SMA 患者治疗后的衍生组织进行分子研究,这限制了我们对应用主要脊髓靶向疗法后仍存在哪些靶点的了解。因此,我们收集了 8 名接受脊柱侧弯手术的 II 型患者和 7 名对照组的椎旁肌肉。我们使用 RNA 序列分析了他们的转录特征,并将其与肌肉组织学相关联。尽管队列规模有限且存在异质性,但我们观察到线粒体氧化磷酸化机制的一致损失、线粒体 DNA 拷贝数的减少,以及细胞压力信号、神经支配和纤维化增加之间的相关性。这项研究为 II 型 SMA 的综合疗法提供了新的假定靶点。
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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 Q1 MEDICINE, RESEARCH & EXPERIMENTAL 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
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.
尽管测序技术不断进步,但许多孟德尔病患者仍无法获得分子诊断。目前的短读临床测序方法在没有进一步样本处理的情况下无法提供染色体相位信息或表观遗传信息,而这并非常规做法,可能导致患者的分子诊断不完整。如果能通过一次测序提供分阶段的遗传和表观遗传信息,就能提高孟德尔疾病的诊断率。在此,我们介绍了使用实时自适应测序方法对孟德尔疾病基因进行靶向长读测序(TaLon-SeqMD)的情况。生物信息学靶向的优化实现了对人类基因组中多个致病区域的选择性富集。在一次测序过程中就能实现单体型解析的变异调用和表观遗传碱基修饰的同步解析。TaLon-SeqMD方法在18名先前针对373个遗传性视网膜疾病(IRD)基因进行过基因检测的受试者队列中进行了验证,在每个案例中都得出了完整的分子诊断结果。该方法还应用于两个检测结果不确定的 IRD 病例,发现了标准短线程测序难以定性的非编码和结构变异。总之,这些结果证明 TaLon-SeqMD 是一种提供快速分阶段变异调用的方法,可为孟德尔疾病提供分子基础。
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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 Q1 MEDICINE, RESEARCH & EXPERIMENTAL 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
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.
通过服用多聚肌苷酸诱发的自身免疫性胰腺炎伴 IgG4 相关疾病(AIP/IgG4-RD)小鼠模型的发病机制尚不完全清楚。虽然已知小鼠和人类 AIP/IgG4-RD 是由产生 IFN-α 的浆细胞状树突状细胞(pDCs)驱动的,但这些细胞的来源及其与效应 T 细胞的关系尚不清楚。在这里,我们发现小鼠的 AIP 是由未发炎胰腺中携带 TLR3 的传统 DCs 启动的,TLR3 配体(聚肌苷酸)激活这些 DCs,导致 IFN-α、CXCL9 和 CXCL10 分泌。这反过来又诱导胰腺招募 CXCR3+ T 细胞,这些 T 细胞通过分泌 CCL25 促进携带 CCR9 的 pDC 向胰腺迁移。这就建立了一个反馈回路,由现在占主导地位的 pDC 产生 IFN-α,CXCR3+ T 细胞继续促进 pDC 迁移。值得注意的是,CXCR3+ T 细胞和 pDC 之间的相互作用也存在于功能层面,因为这种相互作用分别增强了 CXCR3+ T 细胞和 pDC 产生的 CCL25 和 IFN-α。本文提出的证据表明,人类AIP/IgG4-RD也存在类似的疾病机制,这为疾病治疗开辟了新的途径。
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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 Q1 MEDICINE, RESEARCH & EXPERIMENTAL 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

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.

先天性肌无力综合征-22(CMS22,OMIM 616224)是一种罕见的遗传性疾病,由脯氨酰内肽酶样(PREPL)基因的有害遗传变异引起。以往的报告描述了 PREPL 基因缺失和无义变异的患者,但对错义变异在 CMS22 病理学中的影响却一无所知。在本研究中,我们对三名 CMS22 患者的 PREPL 错义变体进行了功能鉴定,这些患者均具有标志性表型。生化评估显示,这些错义变体不会损害水解酶的活性,从而对传统的诊断标准和疾病机制提出了挑战。结构分析表明,这些变体影响的区域很可能涉及蛋白质内部或蛋白质与蛋白质之间的相互作用。事实上,这三种突变体与一组选定的已知相互作用因子的结合率不同程度地降低了。在无催化活性的 PREPL p.Ser559Ala 细胞系中研究了 PREPL 非水解功能的重要性,结果表明 PREPL 的水解活性是正常线粒体功能所必需的,但不是调节 AP1 介导的跨高尔基网络转运所必需的。总之,这些研究表明,CMS22 不仅可由 PREPL 的缺失和截断引起,也可由不一定导致 PREPL 水解活性丧失的错义变体引起。
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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 Q1 MEDICINE, RESEARCH & EXPERIMENTAL 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
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引用次数: 0
Go, Flight. 开始,飞行
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-10 DOI: 10.1172/jci.insight.185748
Oliver Eickelberg
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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 Q1 MEDICINE, RESEARCH & EXPERIMENTAL 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

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.

肺泡巨噬细胞(AMs)是肺部免疫反应的看门人,在识别和消灭病原体方面发挥着重要作用。转录因子(TF)早期生长应答2(EGR2)最近被描述为小鼠成熟AMs的必需因子;然而,它的作用机制尚未被探索。在这里,我们利用表观基因组学方法(RNA 测序、ATAC 测序和 CUT&RUN)确定了 EGR2 是 AMs 中的表观基因组调控因子和可能的直接近端转录激活因子。预测的 EGR2 直接近端靶标包括 AM 特性基因子集,以及与病原体识别、吞噬体成熟和粘附有关的基因,如 Clec7a、Atp6v0d2、Itgb2、Rhoc 和 Tmsb10。我们提供的证据表明,缺乏 EGR2 会导致zymosan 内化受损,并降低对曲霉菌的反应能力。从机理上讲,缺乏 EGR2 会改变体内紫霉素诱导的炎症过程中 AMs 的转录反应、分泌的细胞因子(如 CXCL11)和炎症溶解脂质介质(如 RvE1),表现为溶解能力受损。我们的研究结果表明,EGR2是AMs中一个关键的近端转录激活因子和表观基因组书签,负责选择细胞身份的独特成分以及针对真菌的保护性转录和表观基因组程序。
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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 Q1 MEDICINE, RESEARCH & EXPERIMENTAL 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

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.

人们对不同生物变量(包括生物性别、年龄和性激素)在艾滋病治疗方法中的作用还不甚了解。γc-细胞因子 IL-15 是一种与临床相关的细胞因子,它能促进免疫激活并介导 HIV 从潜伏期重新激活。在这项工作中,我们研究了生物性别、年龄和性激素 17β-雌二醇、孕酮和睾酮可能对 IL-15 的生物活性产生的相互作用。我们发现,女性捐献者与男性捐献者相比,IL-15 介导的 CD4 T 细胞活化程度更高。当 17β-estradiol 浓度较高时,这种差异会减弱。此外,年龄与 IL-15 介导的 CD8 T 细胞活化和 IFN-γ 的产生呈正相关。在潜伏期原代细胞模型中,生物性别、年龄或性激素并不影响 IL-15 重新激活潜伏 HIV 的能力。最后,17β-雌二醇并未持续影响抗逆转录病毒疗法抑制的艾滋病病毒感染者的 CD4 T 细胞中翻译能力库的再激活。我们的研究发现,生理性别和年龄(而非性激素)可能会影响 IL-15 的某些生物活性。了解不同的生物变量如何影响治愈疗法的生物活性,将有助于我们评估目前和未来针对不同人群的艾滋病治愈临床试验。
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引用次数: 0
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