Y染色体造血功能缺失激活免疫检查点,导致衰老细胞清除受损和肾脏疾病

IF 14.6 1区 医学 Q1 CELL BIOLOGY
Yohei Arai, Nicholas W. Chavkin, Yuka Arai, Jonatan Halvardson, Josefin Bjurling, Heather Doviak, Jesse D. Cochran, Megan A. Evans, Keita Horitani, Yoshimitsu Yura, Emiri Miura-Yura, Soichi Sano, Lars A. Forsberg, Kenneth Walsh
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引用次数: 0

摘要

衰老细胞的积累导致发病率和死亡率;然而,支持这种与年龄相关的现象的共同机制仍然难以捉摸。Y染色体造血丧失(LOY)是男性最常见的获得性体细胞突变,这种情况与各种年龄相关疾病和寿命缩短有关。因此,我们研究了造血LOY在促进细胞衰老中的作用,重点关注肾脏疾病,因为它与衰老和衰老有充分的证据。在此,一项前瞻性队列研究显示,血液中的LOY与肾脏疾病的发病率增加有关。对人类肾脏转录特征的分析发现,免疫细胞LOY在肾脏疾病患者中富集,并与更多的细胞衰老有关。在缺乏Y染色体的骨髓重组雄性小鼠中,肾损伤模型和高龄模型的肾功能障碍伴随着衰老细胞的积累。在LOY小鼠中,用一种抗衰老剂治疗可以促进衰老,并优先抑制肾功能障碍的进展。造血LOY导致多种免疫抑制受体上调,针对PD-1(程序性细胞死亡蛋白1)和SIRPα(信号调节蛋白α)的抗体联合治疗可减少肾损伤模型中衰老细胞的积累,并挽救由造血LOY引起的肾脏病理。总的来说,这些数据表明造血LOY通过上调免疫检查点蛋白来损害衰老细胞的清除,从而有助于病理状况。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Hematopoietic loss of Y chromosome activates immune checkpoints and contributes to impaired senescent cell clearance and renal disease
The accumulation of senescent cells contributes to morbidity and mortality; however, common mechanisms underpinning this age-associated phenomenon remain elusive. Hematopoietic loss of the Y chromosome (LOY) is the most frequently acquired somatic mutation in males, and this condition has been associated with various age-associated diseases and reduced lifespan. Therefore, we investigated the role of hematopoietic LOY in promoting cellular senescence, focusing on kidney disease because of its well-documented connection with aging and senescence. Herein, a prospective cohort study revealed that LOY in blood is associated with an increased incidence of kidney diseases. Analyses of transcriptional signatures in human kidneys found that immune cell LOY is enriched in patients with kidney disease and associated with greater amounts of cellular senescence. In male mice reconstituted with bone marrow lacking the Y chromosome, renal dysfunction was accompanied by senescent cell accumulation in models of kidney injury and advanced age. Treatment with a senolytic agent promoted senolysis and preferentially inhibited the progression of renal dysfunction in LOY mice. Hematopoietic LOY led to up-regulation of multiple immune inhibitory receptors, and treatment with the combination of antibodies targeting PD-1 (programmed cell death protein 1) and SIRPα (signal regulatory protein α) reduced senescent cell accumulation and rescued the renal pathology conferred by hematopoietic LOY in the kidney injury model. Collectively, these data indicate that hematopoietic LOY contributes to pathological conditions by impairing the clearance of senescent cells through up-regulation of immune checkpoint proteins.
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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