Macrophage senescence impairs phagocytosis and phagosome function
巨噬细胞衰老损害吞噬作用和吞噬体功能
基本信息
- 批准号:RGPIN-2021-04303
- 负责人:
- 金额:$ 3.64万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2021
- 资助国家:加拿大
- 起止时间:2021-01-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Phagocytosis is an evolutionarily ancient process, which likely originated from the need of single celled organisms to internalize and digest food, and has been preserved as the major mechanism by which macrophages recognize and remove particulates, dying or damaged cells and pathogens. Our lab has recently discovered that non-opsonic phagocytosis (i.e. phagocytosis that does not require the target to be coated by complement, antibodies or other opsonins) by macrophages decreases with age, even though expression of non-opsonic receptors does not change. Furthermore, we have also found age-related changes in the rate of phagolysosomal fusion occur without affecting the pH, proteolytic or oxidative capacity of the phagosome. This delay in phagosome fusion is sufficient to decrease bacterial killing. We have compared the delay of phagolysosomal fusion between macrophages derived from young (20 mo) wildtype (WT) mice and TNF (tumour necrosis factor alpha) knockout mice, and intriguingly, defective macrophage phagocytosis and phagolysosomal maturation does not seem to be due to chronologic age but rather the increase in the inflammatory cytokine TNF. As we age, levels of inflammatory mediators increase in the serum and tissues. Myeloid cells are particularly sensitive to age-associated inflammation. Macrophages derived from old (20+ mo) mice that are deficient in TNF do not lose phagocytic capacity or demonstrate decreased phagolysosomal fusion. By analyzing transcriptional profiles of alveolar macrophages derived from young (3 mo) and old (20+ mo) WT and TNF KO mice, we have found that negative regulators of TNF signalling increase with age in a TNF dependent manner, leading us to hypothesize that this is an adaptation to chronic TNF stimulation that ultimately makes these macrophages less responsive to acute inflammatory events. We have also found that PI3K (phosphoinositide 3-kinase) signalling is compromised in aging macrophages. Although defects in PI3K signalling have been reported in other aging immune cells, the mechanisms by which PI3K signalling is impaired with age in macrophages and the degree to which this impacts phagolysosomal function is not known. Collectively these data support our hypothesis that TNF inhibits phagolysosomal fusion and impairs phagosomal function by increasing expression of negative regulators and altering PI3K signalling pathways. We propose that macrophages do not so much undergo `senescence' (as traditionally described) but rather they adapt to lifelong exposure to the inflammatory microenvironment. This adaptation includes adapting to chronic age-associated inflammation by increasing expression of negative regulators of inflammation. By uncovering specific components of the PI3K and phagolysosomal fusion pathway that are altered by the aging microenvironment, we may uncover whether this unique senescence phenotype is amenable to manipulation.
吞噬作用是一种进化上古老的过程,其可能起源于单细胞生物体内化和消化食物的需要,并且一直被认为是巨噬细胞识别和去除颗粒、死亡或受损细胞和病原体的主要机制。我们的实验室最近发现,巨噬细胞的非调理素吞噬作用(即不需要补体、抗体或其他调理素包被靶标的吞噬作用)随着年龄的增长而降低,即使非调理素受体的表达没有变化。此外,我们还发现,年龄相关的变化发生在吞噬溶酶体融合的速度不影响pH值,蛋白水解或氧化能力的吞噬体。这种吞噬体融合的延迟足以减少细菌杀伤。我们比较了来自年轻(20个月)野生型(WT)小鼠和TNF(肿瘤坏死因子α)基因敲除小鼠的巨噬细胞之间的吞噬溶酶体融合的延迟,有趣的是,缺陷的巨噬细胞吞噬和吞噬溶酶体成熟似乎不是由于年龄,而是炎症细胞因子TNF的增加。随着年龄的增长,血清和组织中炎症介质的水平会增加。骨髓细胞对年龄相关性炎症特别敏感。来自TNF缺乏的老年(20+ mo)小鼠的巨噬细胞未丧失吞噬能力或显示吞噬溶酶体融合减少。通过分析来自年轻(3个月)和老年(20+个月)WT和TNF KO小鼠的肺泡巨噬细胞的转录谱,我们发现TNF信号传导的负调节因子以TNF依赖性方式随着年龄的增长而增加,这使我们假设这是对慢性TNF刺激的适应,最终使这些巨噬细胞对急性炎症事件的反应降低。我们还发现,PI 3 K(磷酸肌醇3-激酶)信号转导在老化的巨噬细胞中受到损害。尽管在其他衰老免疫细胞中已经报道了PI 3 K信号传导的缺陷,但巨噬细胞中PI 3 K信号传导随着年龄的增长而受损的机制以及这对吞噬溶酶体功能的影响程度尚不清楚。总的来说,这些数据支持我们的假设,TNF抑制吞噬溶酶体融合,并通过增加负调节因子的表达和改变PI 3 K信号通路来损害吞噬体功能。我们认为巨噬细胞不会经历太多“衰老”(如传统所述),而是适应终生暴露于炎症微环境。这种适应包括通过增加炎症负调节因子的表达来适应慢性年龄相关性炎症。通过揭示由衰老微环境改变的PI 3 K和吞噬溶酶体融合途径的特定组分,我们可以揭示这种独特的衰老表型是否适合操纵。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Bowdish, Dawn其他文献
Feasibility of pain informed movement program for people with knee osteoarthritis.
- DOI:
10.1016/j.ocarto.2023.100401 - 发表时间:
2023-12 - 期刊:
- 影响因子:0
- 作者:
Modarresi, Shirin;Pearson, Neil;Madden, Kim;Fahnestock, Margaret;Bowdish, Dawn;Carlesso, Lisa C. - 通讯作者:
Carlesso, Lisa C.
Seropositivity and risk factors for SARS-CoV-2 infection in a South Asian community in Ontario: a cross-sectional analysis of a prospective cohort study.
- DOI:
10.9778/cmajo.20220031 - 发表时间:
2022-07 - 期刊:
- 影响因子:0
- 作者:
Anand, Sonia S;Arnold, Corey;Bangdiwala, Shrikant I;Bolotin, Shelly;Bowdish, Dawn;Chanchlani, Rahul;de Souza, Russell J;Desai, Dipika;Kandasamy, Sujane;Khan, Farah;Khan, Zainab;Langlois, Marc-Andre;Limbachia, Jayneel;Lear, Scott A;Loeb, Mark;Loh, Lawrence;Manoharan, Baanu;Nakka, Kiran;Pelchat, Martin;Punthakee, Zubin;Schulze, Karleen M;Williams, Natalie;Wahi, Gita - 通讯作者:
Wahi, Gita
Bowdish, Dawn的其他文献
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{{ truncateString('Bowdish, Dawn', 18)}}的其他基金
Macrophage senescence impairs phagocytosis and phagosome function
巨噬细胞衰老损害吞噬作用和吞噬体功能
- 批准号:
RGPIN-2021-04303 - 财政年份:2022
- 资助金额:
$ 3.64万 - 项目类别:
Discovery Grants Program - Individual
Uncovering mechanisms of phagocytosis by class A scavenger receptors
揭示 A 类清道夫受体的吞噬机制
- 批准号:
RGPIN-2015-05757 - 财政年份:2019
- 资助金额:
$ 3.64万 - 项目类别:
Discovery Grants Program - Individual
Uncovering mechanisms of phagocytosis by class A scavenger receptors
揭示 A 类清道夫受体的吞噬机制
- 批准号:
RGPIN-2015-05757 - 财政年份:2018
- 资助金额:
$ 3.64万 - 项目类别:
Discovery Grants Program - Individual
Uncovering mechanisms of phagocytosis by class A scavenger receptors
揭示 A 类清道夫受体的吞噬机制
- 批准号:
RGPIN-2015-05757 - 财政年份:2017
- 资助金额:
$ 3.64万 - 项目类别:
Discovery Grants Program - Individual
Uncovering mechanisms of phagocytosis by class A scavenger receptors
揭示 A 类清道夫受体的吞噬机制
- 批准号:
RGPIN-2015-05757 - 财政年份:2016
- 资助金额:
$ 3.64万 - 项目类别:
Discovery Grants Program - Individual
Uncovering mechanisms of phagocytosis by class A scavenger receptors
揭示 A 类清道夫受体的吞噬机制
- 批准号:
RGPIN-2015-05757 - 财政年份:2015
- 资助金额:
$ 3.64万 - 项目类别:
Discovery Grants Program - Individual
Novel signalling motifs in macrophage patterm recognition receptors
巨噬细胞模式识别受体中的新信号基序
- 批准号:
386429-2010 - 财政年份:2014
- 资助金额:
$ 3.64万 - 项目类别:
Discovery Grants Program - Individual
Quantitative immunoassay for TLE1 protein
TLE1蛋白的定量免疫分析
- 批准号:
462150-2013 - 财政年份:2013
- 资助金额:
$ 3.64万 - 项目类别:
Engage Grants Program
Novel signalling motifs in macrophage patterm recognition receptors
巨噬细胞模式识别受体中的新信号基序
- 批准号:
386429-2010 - 财政年份:2013
- 资助金额:
$ 3.64万 - 项目类别:
Discovery Grants Program - Individual
Novel signalling motifs in macrophage patterm recognition receptors
巨噬细胞模式识别受体中的新信号基序
- 批准号:
386429-2010 - 财政年份:2012
- 资助金额:
$ 3.64万 - 项目类别:
Discovery Grants Program - Individual
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