Exploring how age impacts the TNF-mediated activation of monocytes

探索年龄如何影响 TNF 介导的单核细胞激活

• 批准号: RGPIN-2022-03931
• 负责人: Verschoor, Chris
• 金额: $ 2.04万
• 依托单位: Laurentian University of Sudbury
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748505
• 关键词: Exploring; how; age; impacts; TNF

Monocytes are pleiotropic myeloid immune cells that play a critical role in the initiation and coordination of innate immune and homeostatic regulatory processes, as well as acting as an important reservoir for specialized immune effector and antigen presenting cells (ie. macrophages and dendritic cells). Although they can be activated through a variety of mechanisms, the cytokine tumour necrosis factor (TNF) is fundamental in the regulation of this process, acting in both a paracrine and autocrine manner. Well-known to amplify and sustain monocyte responses following stimulation, recent work indicates that TNF may also mediate the gradual return to a resting state via the repression of NFkB, a mechanism known as TNF-tolerance. Since TNF can act as both "fuel" and "extinguisher" during monocyte responses, the regulation of mechanisms governing TNF-mediated activation and tolerance is of exceptional importance. Studies performed in a number of mammalian species indicate that monocyte phenotype and function is broadly impacted by aging. However, unlike the common and oversimplified conception that transitions from childhood to adulthood to old age invariably results in a reduction in cellular immune function, monocytes exhibit a variety of alterations with age. One such feature is a dysregulation of canonical signalling pathways such as the aforementioned NFkB, which are often shown to be over-active at a resting state and under-responsive when stimulated; cytokine production generally follows suit. How TNF-signalling is related to these perturbations is very much unknown, but we hypothesize that it plays a fundamental role. Hence, in the following proposal we aim to investigate the dynamics of TNF-mediated activation and tolerance in the regulation of monocytes and how it changes with age. Specifically, we will: 1)Investigate the age-related responses of monocytes to exogenous TNF. 2)Examine the phenotype and TLR-responses of young and old monocytes following TNF pre-exposure. 3)Determine if TNF pre-exposure impacts monocyte to macrophage differentiation and subsequent function. This comprehensive research plan will not only further our knowledge of the regulatory mechanisms governing monocyte activation, it will generate novel findings regarding their evolution with age. Furthermore, it will serve as a multidisciplinary platform for highly qualified personnel (HQP) training in areas such as cellular and molecular biology, immunology, and bioinformatics. Overall, this represents a fundamental component of our overarching goal to advance knowledge of the cross-talk between monocytes and their microenvironment, and specifically, how immunological factors mediate this process.

单核细胞是多效性骨髓免疫细胞，其在先天免疫和稳态调节过程的启动和协调中发挥关键作用，以及充当专门的免疫效应细胞和抗原呈递细胞（即，免疫细胞）的重要储存库。巨噬细胞和树突细胞）。虽然它们可以通过多种机制被激活，但细胞因子肿瘤坏死因子（TNF）在调节这一过程中起重要作用，以旁分泌和自分泌方式起作用。众所周知，在刺激后放大和维持单核细胞反应，最近的工作表明，TNF也可以通过抑制NF κ B介导逐渐恢复到静息状态，这是一种称为TNF耐受的机制。由于TNF在单核细胞反应中既可作为“燃料”又可作为“灭火剂”，因此调节TNF介导的活化和耐受机制具有特别重要的意义。 在许多哺乳动物物种中进行的研究表明，单核细胞表型和功能受到衰老的广泛影响。然而，与从儿童到成年再到老年的过渡总是导致细胞免疫功能降低的常见和过度简化的概念不同，单核细胞随着年龄的增长表现出各种变化。一个这样的特征是典型信号传导途径如上述NFkB的失调，其通常显示在静息状态下过度活跃，而在刺激时反应不足;细胞因子产生通常随之而来。TNF信号如何与这些扰动有关还很不清楚，但我们假设它起着重要作用。因此，在下面的建议中，我们的目的是研究TNF介导的激活和耐受性在单核细胞调节中的动力学以及它如何随年龄变化。具体而言，我们将：1）研究单核细胞对外源性TNF的年龄相关反应。2)检查TNF预暴露后年轻和年老单核细胞的表型和TLR应答。3)确定TNF预暴露是否影响单核细胞向巨噬细胞的分化和随后的功能。 这项全面的研究计划不仅将进一步加深我们对单核细胞激活调控机制的了解，还将产生关于单核细胞随年龄演变的新发现。此外，它还将作为细胞和分子生物学、免疫学和生物信息学等领域高素质人员（HQP）培训的多学科平台。总的来说，这代表了我们总体目标的一个基本组成部分，即促进单核细胞与其微环境之间的相互作用，特别是免疫因子如何介导这一过程。