Immunity & Ageing最新文献_第5页

Activating A1 adenosine receptor signaling boosts early pulmonary neutrophil recruitment in aged mice in response to Streptococcus pneumoniae infection 激活 A1 腺苷受体信号可促进老龄小鼠在肺炎链球菌感染时早期肺中性粒细胞的募集

IF 7.9 2区医学

Immunity & Ageing

Pub Date : 2024-06-05 DOI: 10.1186/s12979-024-00442-3

Shaunna R. Simmons, Sydney E. Herring, Essi Y.I Tchalla, Alexsandra P. Lenhard, Manmeet Bhalla, Elsa N. Bou Ghanem

Streptococcus pneumoniae (pneumococcus) is a leading cause of pneumonia in older adults. Successful control of pneumococci requires robust pulmonary neutrophil influx early in infection. However, aging is associated with aberrant neutrophil recruitment and the mechanisms behind that are not understood. Here we explored how neutrophil recruitment following pneumococcal infection changes with age and the host pathways regulating this. Following pneumococcal infection there was a significant delay in early neutrophil recruitment to the lungs of aged mice. Neutrophils from aged mice showed defects in trans-endothelial migration in vitro compared to young controls. To understand the pathways involved, we examined immune modulatory extracellular adenosine (EAD) signaling, that is activated upon cellular damage. Signaling through the lower affinity A2A and A2B adenosine receptors had no effect on neutrophil recruitment to infected lungs. In contrast, inhibition of the high affinity A1 receptor in young mice blunted neutrophil recruitment to the lungs following infection. A1 receptor inhibition decreased expression of CXCR2 on circulating neutrophils, which is required for trans-endothelial migration. Indeed, A1 receptor signaling on neutrophils was required for their ability to migrate across endothelial cells in response to infection. Aging was not associated with defects in EAD production or receptor expression on neutrophils. However, agonism of A1 receptor in aged mice rescued the early defect in neutrophil migration to the lungs and improved control of bacterial burden. This study suggests age-driven defects in EAD damage signaling can be targeted to rescue the delay in pulmonary neutrophil migration in response to bacterial pneumonia.

肺炎链球菌（肺炎球菌）是导致老年人肺炎的主要原因。要成功控制肺炎球菌，就必须在感染早期让肺部中性粒细胞大量涌入。然而，衰老与中性粒细胞异常招募有关，其背后的机制尚不清楚。在这里，我们探讨了肺炎球菌感染后中性粒细胞的招募是如何随着年龄的增长而发生变化的，以及调节这一变化的宿主途径。肺炎球菌感染后，老年小鼠肺部的早期中性粒细胞募集明显延迟。与年轻对照组相比，老年小鼠的中性粒细胞在体外跨内皮迁移方面表现出缺陷。为了了解其中涉及的途径，我们研究了细胞外腺苷（EAD）信号的免疫调节作用。通过低亲和力 A2A 和 A2B 腺苷受体发出的信号对中性粒细胞招募到受感染肺部没有影响。相反，在幼鼠体内抑制高亲和力的 A1 受体则会阻碍中性粒细胞在感染后被招募到肺部。A1受体抑制降低了循环中性粒细胞上CXCR2的表达，而CXCR2是跨内皮迁移所必需的。事实上，嗜中性粒细胞上的A1受体信号传导是嗜中性粒细胞在感染时跨内皮细胞迁移的必要条件。衰老与中性粒细胞上 EAD 的产生或受体表达的缺陷无关。然而，激动老龄小鼠的 A1 受体可挽救中性粒细胞向肺部迁移的早期缺陷，并改善对细菌负荷的控制。这项研究表明，可以针对年龄驱动的EAD损伤信号传导缺陷来挽救中性粒细胞在应对细菌性肺炎时向肺部迁移的延迟。

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引用次数: 0

The role of blood related inflammatory factors on age-related macular degeneration (AMD) 血液相关炎症因子对老年性黄斑变性（AMD）的作用

IF 7.9 2区医学

Immunity & Ageing

Pub Date : 2024-06-05 DOI: 10.1186/s12979-024-00440-5

Habib Ojaghi, Shirin Poorsheykhian, Amin Najafi, Sohrab Iranpour

Age-related macular degeneration (AMD) is a significant retinal disease that leads to irreversible low vision, particularly in developing countries. The variation in AMD prevalence among different racial groups and highlighted role of inflammation on disease pathology from previous studies which yielded in inconsistent findings, It seems to be of great importance to do more investigation in this field. This case control study involved 204 participants, divided into four groups of equal size (51 individuals per group). Three groups represented AMD cases of varying severity according to Beckman classification (3 groups) and one healthy control group. Sampling was conducted exhaustively until the desired sample size was reached. The control group comprised healthy individuals without any infectious or inflammatory systemic, ophthalmic disease. Blood samples were collected to measure inflammatory factors, including lymphocytes, monocytes, neutrophils, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP). Collected data were analyzed by statistical methods in SPSS version 21. Of the participants, 51% were women, and their ages ranged from 47 to 89 years (62.2 ± 8). According to multiple logistic regression analysis, age exhibited a statistically significant positive association with AMD severity (P = 0.038, odds ratio [OR] = 1.034). ANOVA results indicated a significant association between neutrophil count and AMD severity (P < 0.001). As the disease severity increased, the number of neutrophils decreased. The mean ± SD neutrophil counts for early, intermediate and advanced AMD were 3849 ± 800, 3702 ± 734, and 3342 ± 823, respectively. No statistically significant associations were found between lymphocyte count, monocyte count, neutrophil-to-lymphocyte ratio, CRP, and AMD. There was a significant relationship between the number of neutrophils in peripheral blood and the severity of AMD in study participants which needs more evaluation for the potential utility of this factor in the prognosis of AMD. There was not any significant relationship among the other factors and AMD.

老年性黄斑变性（AMD）是一种严重的视网膜疾病，会导致不可逆的低视力，尤其是在发展中国家。由于不同种族群体的老年黄斑变性发病率存在差异，而且以往的研究强调炎症对疾病病理的作用，但得出的结论并不一致，因此在这一领域开展更多的调查似乎非常重要。这项病例对照研究涉及 204 名参与者，分为四组，每组 51 人，每组人数相等。根据贝克曼分类法，三组代表不同严重程度的 AMD 病例（3 组），另一组为健康对照组。抽样工作一直持续到达到所需的样本量为止。对照组由没有任何感染性或炎症性系统性眼科疾病的健康人组成。采集的血液样本用于测量炎症因子，包括淋巴细胞、单核细胞、中性粒细胞、中性粒细胞与淋巴细胞比值（NLR）和 C 反应蛋白（CRP）。收集的数据采用 SPSS 21 版的统计方法进行分析。在参与者中，51%为女性，年龄在47至89岁之间（62.2 ± 8）。根据多元逻辑回归分析，年龄与 AMD 严重程度呈显著正相关（P = 0.038，几率比 [OR] = 1.034）。方差分析结果表明，中性粒细胞计数与 AMD 严重程度有明显的相关性（P < 0.001）。随着疾病严重程度的增加，中性粒细胞的数量也随之减少。早期、中期和晚期AMD中性粒细胞计数的平均值（±SD）分别为3849±800、3702±734和3342±823。淋巴细胞计数、单核细胞计数、中性粒细胞与淋巴细胞比率、CRP与AMD之间没有统计学意义上的关联。研究参与者外周血中的中性粒细胞数量与老年性黄斑病变的严重程度有明显关系，需要进一步评估这一因素在老年性黄斑病变预后中的潜在作用。其他因素与老年性黄斑病变之间没有明显关系。

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引用次数: 0

Chemokine receptor 7 contributes to T- and B-cell filtering in ageing bladder, cystitis and bladder cancer. 趋化因子受体 7 对老化膀胱、膀胱炎和膀胱癌中的 T 细胞和 B 细胞过滤有促进作用。

IF 7.9 2区医学

Immunity & Ageing

Pub Date : 2024-05-18 DOI: 10.1186/s12979-024-00432-5

Jiang Zhao, Xing Luo, Chengfei Yang, Xiao Yang, Min Deng, Bishao Sun, Jingzhen Zhu, Zongming Dong, Yangcai Wang, Jia Li, Xingliang Yang, Benyi Li, Xiangwei Wang, Ji Zheng

Background: Research has suggested significant correlations among ageing, immune microenvironment, inflammation and tumours. However, the relationships among ageing, immune microenvironment, cystitis and bladder urothelial carcinoma (BLCA) in the bladder have rarely been reported.

Methods: Bladder single-cell and transcriptomic data from young and old mice were used for immune landscape analysis. Transcriptome, single-cell and The Cancer Genome Atlas Program datasets of BLCA and interstitial cystitis/bladder pain syndrome (IC/BPS) were used to analyse immune cell infiltration and molecular expression. Bladder tissues from mice, IC/BPS and BLCA were collected to validate the results.

Results: Eight types of immune cells (macrophages, B-cells, dendritic cells, T-cells, monocytes, natural killer cells, γδ T-cells and ILC2) were identified in the bladder of mice. Aged mice bladder tissues had a significantly higher number of T-cells, γδ T-cells, ILC2 and B-cells than those in the young group (P < 0.05). Three types of T-cells (NK T-cells, γδ T-cells and naïve T-cells) and three types of B-cells (follicular B-cells, plasma and memory B-cells) were identified in aged mice bladder. Chemokine receptor 7 (CCR7) is highly expressed in aged bladder, IC/BPS and BLCA (P < 0.05). CCR7 is likely to be involved in T- and B-cell infiltration in aged bladder, IC/BPS and BLCA. Interestingly, the high CCR7 expression on BLCA cell membranes was a prognostic protective factor.

Conclusions: In this study, we characterised the expression profiles of immune cells in bladder tissues of aged and young mice and demonstrated that CCR7-mediated T- and B-cell filtration contributes to the development of bladder ageing, IC/BPS and BLCA.

背景：研究表明，衰老、免疫微环境、炎症和肿瘤之间存在明显的相关性。然而，有关膀胱衰老、免疫微环境、膀胱炎和膀胱尿路上皮癌（BLCA）之间关系的研究却鲜有报道：方法：利用年轻小鼠和老年小鼠的膀胱单细胞和转录组数据进行免疫景观分析。利用BLCA和间质性膀胱炎/膀胱疼痛综合征（IC/BPS）的转录组、单细胞和癌症基因组图谱计划数据集分析免疫细胞浸润和分子表达。收集了小鼠、IC/BPS 和 BLCA 的膀胱组织来验证结果：结果：在小鼠膀胱中发现了八种类型的免疫细胞（巨噬细胞、B 细胞、树突状细胞、T 细胞、单核细胞、自然杀伤细胞、γδ T 细胞和 ILC2）。老龄小鼠膀胱组织中的 T 细胞、γδ T 细胞、ILC2 和 B 细胞数量明显高于年轻组（P 结论：老龄小鼠膀胱组织中的 T 细胞、γδ T 细胞、ILC2 和 B 细胞数量明显高于年轻组（P）：在这项研究中，我们分析了老龄小鼠和年轻小鼠膀胱组织中免疫细胞的表达谱，并证明了 CCR7 介导的 T 细胞和 B 细胞滤过是膀胱老化、IC/BPS 和 BLCA 发展的原因。

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引用次数: 0

The neutrophil to lymphocyte ratio associates with markers of Alzheimer's disease pathology in cognitively unimpaired elderly people. 中性粒细胞与淋巴细胞的比率与认知能力未受损的老年人阿尔茨海默病病理标志物有关。

IF 7.9 2区医学

Immunity & Ageing

Pub Date : 2024-05-17 DOI: 10.1186/s12979-024-00435-2

Tovia Jacobs, Sean R Jacobson, Juan Fortea, Jeffrey S Berger, Alok Vedvyas, Karyn Marsh, Tianshe He, Eugenio Gutierrez-Jimenez, Nathanael R Fillmore, Moses Gonzalez, Luisa Figueredo, Naomi L Gaggi, Chelsea Reichert Plaska, Nunzio Pomara, Esther Blessing, Rebecca Betensky, Henry Rusinek, Henrik Zetterberg, Kaj Blennow, Lidia Glodzik, Thomas M Wisniweski, Mony J de Leon, Ricardo S Osorio, Jaime Ramos-Cejudo

Background: An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau₁₈₁ (p-tau), as well as the trajectories of these CSF measures obtained longitudinally.

Results: A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data.

Conclusions: We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.

背景：血液中中性粒细胞-淋巴细胞比率（NLR）升高与阿尔茨海默病（AD）有关。然而，NLR 升高也与许多其他疾病有关，而这些疾病都是导致阿尔茨海默病的风险因素，这促使人们研究 NLR 是直接与阿尔茨海默病的病理变化有关，还是潜在合并症的结果。在此，我们探讨了 NLR 与认知功能未受损（CU）受试者脑脊液（CSF）中的 AD 生物标志物之间的关系。在对社会人口统计学、APOE4 和常见合并症进行调整后，我们在两个队列中研究了这些关联：阿尔茨海默病神经影像学倡议（ADNI）和纽约大学的 M.J. de Leon CSF 储存库。具体来说，我们研究了NLR与淀粉样蛋白-β42（Aβ42）、总tau（t-tau）和磷酸化tau181（p-tau）的横断面测量值之间的关系，以及纵向获得的这些CSF测量值的轨迹：共纳入111名ADNI参与者和190名纽约大学参与者，他们被归类为CU，并提供了NLR、CSF和协变量数据。与纽约大学相比，ADNI 参与者的年龄更大（73.79 岁对 61.53 岁，P 结论：ADNI 参与者的年龄与 NLR 和 CSF 的相关性更大：我们报告了年龄较大的 ADNI 群体中 NLR 与 Aβ42 之间的关系，以及较年轻的纽约大学群体中 NLR 与 t-tau 和 p-tau 之间的关系。在对合并症进行调整后，两者之间的关系依然存在，这表明 NLR 与 AD 之间存在直接联系。不过，NLR与特定AD生物标志物之间的关联变化可能是免疫衰老的一部分。

{"title":"The neutrophil to lymphocyte ratio associates with markers of Alzheimer's disease pathology in cognitively unimpaired elderly people.","authors":"Tovia Jacobs, Sean R Jacobson, Juan Fortea, Jeffrey S Berger, Alok Vedvyas, Karyn Marsh, Tianshe He, Eugenio Gutierrez-Jimenez, Nathanael R Fillmore, Moses Gonzalez, Luisa Figueredo, Naomi L Gaggi, Chelsea Reichert Plaska, Nunzio Pomara, Esther Blessing, Rebecca Betensky, Henry Rusinek, Henrik Zetterberg, Kaj Blennow, Lidia Glodzik, Thomas M Wisniweski, Mony J de Leon, Ricardo S Osorio, Jaime Ramos-Cejudo","doi":"10.1186/s12979-024-00435-2","DOIUrl":"10.1186/s12979-024-00435-2","url":null,"abstract":"Background: An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally.Results: A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data.Conclusions: We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11100119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140960200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Correction: The interplay between obesity, immunosenescence, and insulin resistance. 更正：肥胖、免疫衰老和胰岛素抵抗之间的相互作用。

IF 7.9 2区医学

Immunity & Ageing

Pub Date : 2024-05-15 DOI: 10.1186/s12979-024-00438-z

Ghazaleh Shimi, Mohammad Hassan Sohouli, Arman Ghorbani, Azam Shakery, Hamid Zand

引用次数: 0

Irisin inhibits microglial senescence via TFAM-mediated mitochondrial metabolism in a mouse model of tauopathy. 鸢尾素通过TFAM介导的线粒体新陈代谢抑制小鼠脑干胶质细胞衰老。

IF 7.9 2区医学

Immunity & Ageing

Pub Date : 2024-05-14 DOI: 10.1186/s12979-024-00437-0

Cailin Wang, Xiufeng Wang, Shangqi Sun, Yanmin Chang, Piaopiao Lian, Hongxiu Guo, Siyi Zheng, Rong Ma, Gang Li

Background: The accumulation of senescent microglia has been highlighted as a critical contributor to the progression of tauopathies. Irisin, a muscle-derived hormone produced by the proteolytic cleavage of Fibronectin-domain III containing 5 (FNDC5), mediates the pleiotropic effects of exercise on the physical body. Herein, we investigate the potential role of irisin in microglial senescence in tauopathies.

Methods: To model tauopathies both in vivo and in vitro, we utilized P301S tau transgenic mice and tau K18 fibril-treated microglia BV2 cells, respectively. We first examined the expression of the irisin expression and senescence phenotypes of microglia in tauopathies. Subsequently, we investigated the impact of irisin on microglial senescence and its underlying molecular mechanisms.

Result: We observed a reduction in irisin levels and an onset of premature microglial senescence both in vivo and in vitro. Irisin administration was found to counteract microglial senescence and ameliorate cognitive decline in P301S mice. Mechanistically, irisin effectively inhibited microglial senescence by stimulating the expression of mitochondrial transcription factor A (TFAM), a master regulator of mitochondrial respiratory chain biogenesis, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS). Silencing TFAM eliminated the inhibitory effect of irisin on microglial senescence as well as the restorative effect of irisin on mitochondrial OXPHOS. Furthermore, the SIRT1/PGC1α signaling pathway appeared to be implicated in irisin-mediated upregulation of TFAM.

Conclusion: Taken together, our study revealed that irisin mitigated microglial senescence via TFAM-driven mitochondrial biogenesis, suggesting a promising new avenue for therapeutic strategies targeting tauopathies.

背景：衰老小胶质细胞的积累已被强调为导致陶陶病进展的一个关键因素。鸢尾素是一种肌肉源性荷尔蒙，由含有纤连蛋白-结构域III的5（FNDC5）蛋白水解产生，它介导了运动对身体的多重效应。在此，我们研究了鸢尾素在tauopathies小胶质细胞衰老中的潜在作用：为了在体内和体外模拟tau病，我们分别利用了P301S tau转基因小鼠和tau K18纤维处理的小胶质细胞BV2。我们首先研究了tau病中小胶质细胞的鸢尾素表达和衰老表型。随后，我们研究了鸢尾素对小胶质细胞衰老的影响及其潜在的分子机制：结果：我们在体内和体外都观察到了鸢尾素水平的降低和小胶质细胞过早衰老的开始。结果：我们在体内和体外都观察到了鸢尾素水平的降低和小胶质细胞过早衰老的发生，并发现鸢尾素能抵消小胶质细胞的衰老并改善 P301S 小鼠的认知能力下降。从机理上讲，鸢尾素通过刺激线粒体转录因子 A（线粒体呼吸链生物生成的主调节因子）的表达，从而增强线粒体氧化磷酸化（OXPHOS），有效抑制了小胶质细胞的衰老。沉默 TFAM 可消除鸢尾素对小胶质细胞衰老的抑制作用以及鸢尾素对线粒体氧化磷酸化的恢复作用。此外，SIRT1/PGC1α信号通路似乎与鸢尾素介导的TFAM上调有关：综上所述，我们的研究揭示了鸢尾素通过TFAM驱动的线粒体生物生成减轻了小胶质细胞的衰老，这为针对tauopathies的治疗策略提供了一条很有前景的新途径。

{"title":"Irisin inhibits microglial senescence via TFAM-mediated mitochondrial metabolism in a mouse model of tauopathy.","authors":"Cailin Wang, Xiufeng Wang, Shangqi Sun, Yanmin Chang, Piaopiao Lian, Hongxiu Guo, Siyi Zheng, Rong Ma, Gang Li","doi":"10.1186/s12979-024-00437-0","DOIUrl":"10.1186/s12979-024-00437-0","url":null,"abstract":"Background: The accumulation of senescent microglia has been highlighted as a critical contributor to the progression of tauopathies. Irisin, a muscle-derived hormone produced by the proteolytic cleavage of Fibronectin-domain III containing 5 (FNDC5), mediates the pleiotropic effects of exercise on the physical body. Herein, we investigate the potential role of irisin in microglial senescence in tauopathies.Methods: To model tauopathies both in vivo and in vitro, we utilized P301S tau transgenic mice and tau K18 fibril-treated microglia BV2 cells, respectively. We first examined the expression of the irisin expression and senescence phenotypes of microglia in tauopathies. Subsequently, we investigated the impact of irisin on microglial senescence and its underlying molecular mechanisms.Result: We observed a reduction in irisin levels and an onset of premature microglial senescence both in vivo and in vitro. Irisin administration was found to counteract microglial senescence and ameliorate cognitive decline in P301S mice. Mechanistically, irisin effectively inhibited microglial senescence by stimulating the expression of mitochondrial transcription factor A (TFAM), a master regulator of mitochondrial respiratory chain biogenesis, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS). Silencing TFAM eliminated the inhibitory effect of irisin on microglial senescence as well as the restorative effect of irisin on mitochondrial OXPHOS. Furthermore, the SIRT1/PGC1α signaling pathway appeared to be implicated in irisin-mediated upregulation of TFAM.Conclusion: Taken together, our study revealed that irisin mitigated microglial senescence via TFAM-driven mitochondrial biogenesis, suggesting a promising new avenue for therapeutic strategies targeting tauopathies.","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11092051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Quercetin promotes the proportion and maturation of NK cells by binding to MYH9 and improves cognitive functions in aged mice. 槲皮素通过与 MYH9 结合促进 NK 细胞的比例和成熟，并改善老年小鼠的认知功能。

IF 7.9 2区医学

Immunity & Ageing

Pub Date : 2024-05-10 DOI: 10.1186/s12979-024-00436-1

Tingting Su, Haitao Shen, Mengyuan He, Shanshan Yang, Xue Gong, Ce Huang, Liuling Guo, Hao Wang, Shengyu Feng, Taotao Mi, Meili Zhao, Qing Liu, Fengjiao Huo, Jian-Kang Zhu, Jianbo Zhu, Hongbin Li, Hailiang Liu

Background: Quercetin is a flavonol compound widely distributed in plants that possesses diverse biological properties, including antioxidative, anti-inflammatory, anticancer, neuroprotective and senescent cell-clearing activities. It has been shown to effectively alleviate neurodegenerative diseases and enhance cognitive functions in various models. The immune system has been implicated in the regulation of brain function and cognitive abilities. However, it remains unclear whether quercetin enhances cognitive functions by interacting with the immune system.

Results: In this study, middle-aged female mice were administered quercetin via tail vein injection. Quercetin increased the proportion of NK cells, without affecting T or B cells, and improved cognitive performance. Depletion of NK cells significantly reduces cognitive ability in mice. RNA-seq analysis revealed that quercetin modulated the RNA profile of hippocampal tissues in aging animals towards a more youthful state. In vitro, quercetin significantly inhibited the differentiation of Lin^-CD117⁺ hematopoietic stem cells into NK cells. Furthermore, quercetin promoted the proportion and maturation of NK cells by binding to the MYH9 protein.

Conclusions: In summary, our findings suggest that quercetin promotes the proportion and maturation of NK cells by binding to the MYH9 protein, thereby improving cognitive performance in middle-aged mice.

背景：槲皮素是一种广泛分布于植物中的黄酮醇化合物，具有多种生物特性，包括抗氧化、抗炎、抗癌、神经保护和清除衰老细胞等活性。研究表明，它能有效缓解神经退行性疾病，并在各种模型中增强认知功能。免疫系统与大脑功能和认知能力的调节有关。然而，槲皮素是否能通过与免疫系统相互作用来增强认知功能，目前仍不清楚：在这项研究中，中年雌性小鼠通过尾静脉注射槲皮素。槲皮素增加了 NK 细胞的比例，但不影响 T 细胞或 B 细胞，并改善了认知能力。消耗NK细胞会大大降低小鼠的认知能力。RNA-seq分析表明，槲皮素能调节衰老动物海马组织的RNA谱，使其趋于年轻化。在体外，槲皮素明显抑制了Lin-CD117+造血干细胞向NK细胞的分化。此外，槲皮素还能通过与MYH9蛋白结合促进NK细胞的比例和成熟：综上所述，我们的研究结果表明，槲皮素可通过与MYH9蛋白结合促进NK细胞的比例和成熟，从而改善中年小鼠的认知能力。

{"title":"Quercetin promotes the proportion and maturation of NK cells by binding to MYH9 and improves cognitive functions in aged mice.","authors":"Tingting Su, Haitao Shen, Mengyuan He, Shanshan Yang, Xue Gong, Ce Huang, Liuling Guo, Hao Wang, Shengyu Feng, Taotao Mi, Meili Zhao, Qing Liu, Fengjiao Huo, Jian-Kang Zhu, Jianbo Zhu, Hongbin Li, Hailiang Liu","doi":"10.1186/s12979-024-00436-1","DOIUrl":"10.1186/s12979-024-00436-1","url":null,"abstract":"Background: Quercetin is a flavonol compound widely distributed in plants that possesses diverse biological properties, including antioxidative, anti-inflammatory, anticancer, neuroprotective and senescent cell-clearing activities. It has been shown to effectively alleviate neurodegenerative diseases and enhance cognitive functions in various models. The immune system has been implicated in the regulation of brain function and cognitive abilities. However, it remains unclear whether quercetin enhances cognitive functions by interacting with the immune system.Results: In this study, middle-aged female mice were administered quercetin via tail vein injection. Quercetin increased the proportion of NK cells, without affecting T or B cells, and improved cognitive performance. Depletion of NK cells significantly reduces cognitive ability in mice. RNA-seq analysis revealed that quercetin modulated the RNA profile of hippocampal tissues in aging animals towards a more youthful state. In vitro, quercetin significantly inhibited the differentiation of Lin-CD117+ hematopoietic stem cells into NK cells. Furthermore, quercetin promoted the proportion and maturation of NK cells by binding to the MYH9 protein.Conclusions: In summary, our findings suggest that quercetin promotes the proportion and maturation of NK cells by binding to the MYH9 protein, thereby improving cognitive performance in middle-aged mice.","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11084035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140905144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Increased levels of GM-CSF and CXCL10 and low CD8⁺ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people. GM-CSF 和 CXCL10 水平的升高以及 CD8+ 记忆干 T 细胞数量的减少是老年人免疫衰老和严重 COVID-19 的标志。

IF 7.9 2区医学

Immunity & Ageing

Pub Date : 2024-05-07 DOI: 10.1186/s12979-024-00430-7

Johanne Poisson, Carine El-Sissy, Arnaud Serret-Larmande, Nikaïa Smith, Morgane Lebraud, Jean-Loup Augy, Catherine Conti, Cécile Gonnin, Benjamin Planquette, Jean-Benoît Arlet, Bertrand Hermann, Bruno Charbit, Jean Pastre, Floriane Devaux, Cyrielle Ladavière, Lydie Lim, Pauline Ober, Johanna Cannovas, Lucie Biard, Marie-Christelle Gulczynski, Noémie Blumenthal, Hélène Péré, Camille Knosp, Alain Gey, Nadine Benhamouda, Juliette Murris, David Veyer, Eric Tartour, Jean-Luc Diehl, Darragh Duffy, Elena Paillaud, Clémence Granier

Background: Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8⁺ T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity.

Results: One hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1β, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8⁺T cells, and (ii) decreased early precursors CD8⁺ T stem cell-like memory cells (TSCM) and CD27⁺CD28⁺. The cytokines mentioned above were found at higher concentrations in the COVID-19⁺ older cohort compared to a younger cohort in which they were not associated with disease severity.

Conclusions: Our results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care.

背景：衰老会导致免疫反应的改变，从而使老年人更容易受到某些感染。免疫老化是一个异质性过程，也与炎症老化（一种低度慢性炎症）有关。以前在严重的 COVID-19 病例中描述过细胞毒性 T 细胞反应的改变和细胞因子风暴，但导致这种免疫反应失败的参数尚不十分清楚。我们的研究旨在根据 COVID-19 的严重程度对 70 岁以上的患者进行分层，以确定与衰老相关的 CD8+ T 细胞和细胞因子的特征：研究共纳入了 144 名患者。我们发现，在老年人中，COVID-19 严重程度与以下因素有关：(i) GM-CSF、CXCL10 (IP-10)、VEGF、IL-1β、CCL2 (MCP-1) 和中性粒细胞与淋巴细胞比值 (NLR) 水平较高；(ii) 终末分化的 CD8+T 细胞增多；(ii) 早期前体 CD8+ T 干细胞样记忆细胞 (TSCM) 和 CD27+CD28+ 减少。上述细胞因子在 COVID-19+ 老年组群中的浓度较高，而在年轻组群中则与疾病严重程度无关：我们的研究结果凸显了髓系在老年人 COVID-19 严重程度中的特殊重要性。由于GM-CSF和CXCL10与年轻患者的COVID-19严重程度无关，因此它们可能代表了疾病严重程度的老化特异性标志物，应在老年人护理中加以考虑。

{"title":"Increased levels of GM-CSF and CXCL10 and low CD8+ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people.","authors":"Johanne Poisson, Carine El-Sissy, Arnaud Serret-Larmande, Nikaïa Smith, Morgane Lebraud, Jean-Loup Augy, Catherine Conti, Cécile Gonnin, Benjamin Planquette, Jean-Benoît Arlet, Bertrand Hermann, Bruno Charbit, Jean Pastre, Floriane Devaux, Cyrielle Ladavière, Lydie Lim, Pauline Ober, Johanna Cannovas, Lucie Biard, Marie-Christelle Gulczynski, Noémie Blumenthal, Hélène Péré, Camille Knosp, Alain Gey, Nadine Benhamouda, Juliette Murris, David Veyer, Eric Tartour, Jean-Luc Diehl, Darragh Duffy, Elena Paillaud, Clémence Granier","doi":"10.1186/s12979-024-00430-7","DOIUrl":"10.1186/s12979-024-00430-7","url":null,"abstract":"Background: Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8+ T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity.Results: One hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1β, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8+T cells, and (ii) decreased early precursors CD8+ T stem cell-like memory cells (TSCM) and CD27+CD28+. The cytokines mentioned above were found at higher concentrations in the COVID-19+ older cohort compared to a younger cohort in which they were not associated with disease severity.Conclusions: Our results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care.","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11075216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140877910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Sexual dimorphism in atherosclerotic plaques of aged Ldlr−/− mice 老年 Ldlr-/- 小鼠动脉粥样硬化斑块的性别双态性

IF 7.9 2区医学

Immunity & Ageing

Pub Date : 2024-05-02 DOI: 10.1186/s12979-024-00434-3

Virginia Smit, Jill de Mol, Mireia N. A. Bernabé Kleijn, Marie A. C. Depuydt, Menno P. J. de Winther, Ilze Bot, Johan Kuiper, Amanda C. Foks

Atherosclerosis, the main underlying pathology of cardiovascular disease, is a chronic inflammatory disease characterized by lipid accumulation and immune cell responses in the vascular wall, resulting in plaque formation. It is well-known that atherosclerosis prevalence and manifestation vary by sex. However, sexual dimorphism in the immune landscape of atherosclerotic plaques has up to date not been studied at high-resolution. In this study, we investigated sex-specific differences in atherosclerosis development and the immunological landscape of aortas at single-cell level in aged Ldlr−/− mice. We compared plaque morphology between aged male and female chow diet-fed Ldlr−/− mice (22 months old) with histological analysis. Using single-cell RNA-sequencing and flow cytometry on CD45+ immune cells from aortas of aged Ldlr−/− mice, we explored the immune landscape in the atherosclerotic environment in males and females. We show that plaque volume is comparable in aged male and female mice, and that plaques in aged female mice contain more collagen and cholesterol crystals, but less necrotic core and macrophage content compared to males. We reveal increased immune cell infiltration in female aortas and found that expression of pro-atherogenic markers and inflammatory signaling pathways was enriched in plaque immune cells of female mice. Particularly, female aortas show enhanced activation of B cells (Egr1, Cd83, Cd180), including age-associated B cells, in addition to an increased M1/M2 macrophage ratio, where Il1b+ M1-like macrophages display a more pro-inflammatory phenotype (Nlrp3, Cxcl2, Mmp9) compared to males. In contrast, increased numbers of age-associated Gzmk+CD8+ T cells, dendritic cells, and Trem2+ macrophages were observed in male aortas. Altogether, our findings highlight that sex is a variable that contributes to immunological differences in the atherosclerotic plaque environment in mice and provide valuable insights for further preclinical studies into the impact of sex on the pathophysiology of atherosclerosis.

动脉粥样硬化是心血管疾病的主要病理基础，是一种慢性炎症性疾病，其特征是血管壁上的脂质堆积和免疫细胞反应，从而形成斑块。众所周知，动脉粥样硬化的发病率和表现因性别而异。然而，迄今为止，人们尚未对动脉粥样硬化斑块免疫景观的性别二态性进行高分辨率研究。在这项研究中，我们在单细胞水平上研究了老年 Ldlr-/- 小鼠动脉粥样硬化发展和主动脉免疫景观的性别差异。我们通过组织学分析比较了以饲料喂养的雌雄 Ldlr-/- 小鼠（22 个月大）的斑块形态。我们使用单细胞 RNA 序列分析和流式细胞术检测了老年 Ldlr-/- 小鼠主动脉中的 CD45+ 免疫细胞，探索了雌雄小鼠动脉粥样硬化环境中的免疫格局。我们发现，老年雌雄小鼠的斑块体积相当，与雄性小鼠相比，老年雌性小鼠的斑块含有更多的胶原蛋白和胆固醇结晶，但坏死核心和巨噬细胞含量较少。我们发现雌性小鼠主动脉中的免疫细胞浸润增加，并发现雌性小鼠斑块免疫细胞中富含促动脉粥样硬化标志物和炎症信号通路的表达。与雄性相比，雌性小鼠主动脉中的B细胞（Egr1、Cd83、Cd180）（包括年龄相关的B细胞）活化增强，此外，M1/M2巨噬细胞比例增加，其中Il1b+ M1样巨噬细胞显示出更多的促炎症表型（Nlrp3、Cxcl2、Mmp9）。相反，在男性主动脉中观察到与年龄相关的 Gzmk+CD8+ T 细胞、树突状细胞和 Trem2+ 巨噬细胞数量增加。总之，我们的研究结果突出表明，性别是导致小鼠动脉粥样硬化斑块环境免疫学差异的一个变量，并为进一步临床前研究性别对动脉粥样硬化病理生理学的影响提供了宝贵的见解。

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The effect of T cell aging on the change of human tissue structure T 细胞老化对人体组织结构变化的影响

IF 7.9 2区医学

Immunity & Ageing

Pub Date : 2024-04-30 DOI: 10.1186/s12979-024-00433-4

Ling-ling Xu, Xiang Chen, Jing-ping Cheng

The trend of aging of the global population is becoming more and more significant, and the incidence of age-related diseases continues to rise.This phenomenon makes the problem of aging gradually attracted wide attention of the society, and gradually developed into an independent research field.As a vital defense mechanism of the human body, the immune system changes significantly during the aging process.Age-induced changes in the body’s immune system are considered harmful and are commonly referred to as immune aging, which may represent the beginning of systemic aging.Immune cells, especially T cells, are the biggest influencers and participants in age-related deterioration of immune function, making older people more susceptible to different age-related diseases.More and more evidence shows that T cells play an important role in the change of human tissue structure after aging, which fundamentally affects the health and survival of the elderly.In this review, we discuss the general characteristics of age-related T cell immune alterations and the possible effects of aging T cells in various tissue structures in the human body.

全球人口老龄化趋势日益显著，老年性疾病发病率持续上升，这一现象使得老龄化问题逐渐引起社会的广泛关注，并逐渐发展成为一个独立的研究领域。作为人体重要的防御机制，免疫系统在老龄化过程中会发生显著变化，由年龄引起的机体免疫系统变化被认为是有害的，通常被称为免疫衰老，它可能代表着全身衰老的开始。越来越多的证据表明，T 细胞在衰老后人体组织结构的变化中扮演着重要角色，从根本上影响着老年人的健康和生存。在这篇综述中，我们讨论了与年龄相关的 T 细胞免疫改变的一般特征，以及衰老的 T 细胞对人体各种组织结构可能产生的影响。

引用次数: 0