AGING AND APOPTOTIC MODULATION OF IMMUNE RESPONSIVENESS

免疫反应的衰老和细胞凋亡调节

• 批准号: 6938469
• 负责人: DAVID S UCKER
• 金额: $ 15.32万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6938469
• 关键词: age difference; aging; antigen presenting cell; apoptosis; cell cell interaction; cell senescence; cytokine; immune response; immunomodulators; immunosenescence; inflammation; laboratory mouse; macrophage; phagocytosis; vesicle /vacuole

DESCRIPTION (provided by applicant): Immunosenescence is characterized by paradoxical alterations in adaptive and innate immune responsiveness. Striking increases in the inflammatory status of many individuals with age - even in the absence of overt infection - and the diminished ability to modulate those responses have been implicated causally in the pathogenesis of a variety of aging-associated disorders, and may be involved centrally in all aspects of aging-associated immune dysfunction. In this context, potential changes with age in the anti-inflammatory effects of apoptotic cells have not been considered previously. Our recent studies have demonstrated the profound ability of apoptotic cells to modulate the pro-inflammatory responses of macrophages with which they interact. The modulatory activity of the apoptotic corpse, representing a gain-of-function acquired during the physiological cell death process, is manifest as an immediate-early inhibition of pro-inflammatory cytokine gene transcription within the engulfing macrophage, and is exerted upon binding to the macrophage, independent of subsequent engulfment. Recognition and inflammatory modulation represent key elements of an innate immune response, independent of Toll-like receptor signaling, that discriminates live from effete cells. We hypothesize that the extent of immune modulation exerted by apoptotic cells may be altered in an aging-associated manner, and that these changes underlie and exacerbate the paradoxical and pathological alterations of immunosenescence. The exploratory experiments proposed in this application will test this novel hypothesis by examining, as a function of animal age, the interactions in vivo of macrophages with apoptotic cells, as well as the consequences of those interactions with respect to a variety of innate macrophage immune responses, employing rigorous quantitative approaches. We will evaluate directly whether the abilities of macrophages to interact with and engulf apoptotic cells and consequently to modulate their inflammatory and other immune responses are altered in an aging-associated manner. We will test as well the ability of exogenous apoptotic modulators to attenuate inflammatory responses in vivo as a function of animal age. A fuller understanding of the process of immune modulation exerted physiologically by apoptotic cells has enormous significance for efforts to intervene in cases of deleterious and pathological inflammatory responses that underlie and exacerbate immunosenescence.

描述(由申请人提供)：免疫衰老的特征是适应性和先天免疫反应性的矛盾变化。许多人的炎症状态随着年龄的增长而显著增加-即使在没有明显感染的情况下-以及调节这些反应的能力减弱已被认为是各种与衰老相关的疾病的发病机制之一，并可能集中参与与衰老相关的免疫功能障碍的方方面面。在这种背景下，以前还没有考虑过凋亡细胞的抗炎作用随年龄的潜在变化。我们最近的研究表明，凋亡细胞具有深刻的能力来调节与其相互作用的巨噬细胞的促炎反应。凋亡身体的调节活性代表着在生理细胞死亡过程中获得的功能获得，表现为对吞噬的巨噬细胞内的促炎细胞因子基因转录的即时早期抑制，并在与巨噬细胞结合时发挥作用，而不依赖于随后的吞噬。识别和炎症调节是先天免疫反应的关键要素，独立于Toll样受体信号，区分活细胞和衰弱细胞。我们假设，凋亡细胞所发挥的免疫调节作用的程度可能会以一种与衰老相关的方式发生变化，这些变化是免疫衰老矛盾和病理变化的基础和加剧。本申请中提出的探索性实验将使用严格的定量方法，通过检查巨噬细胞与凋亡细胞在体内的相互作用，以及这些相互作用对各种天然巨噬细胞免疫反应的影响，来检验这一新的假设。我们将直接评估巨噬细胞与凋亡细胞相互作用并吞噬细胞从而调节其炎症和其他免疫反应的能力是否会以与衰老相关的方式发生改变。我们还将测试外源性凋亡调节剂在体内减弱炎症反应的能力，作为动物年龄的函数。更全面地了解凋亡细胞在生理上实施的免疫调节过程，对于努力干预作为免疫衰老基础和恶化基础的有害和病理性炎症反应具有巨大的意义。

项目成果

Apoptotic and necrotic cells as sentinels of local tissue stress and inflammation: response pathways initiated in nearby viable cells.

凋亡和坏死细胞作为局部组织应激和炎症的哨兵：在附近活细胞中启动的反应途径。

• DOI: 10.1080/08916930902832124
• 发表时间: 2009
• 期刊: Autoimmunity
• 影响因子: 3.5
• 作者: Patel,VimalA;Lee,DanielJ;Longacre-Antoni,Angelika;Feng,Lanfei;Lieberthal,Wilfred;Rauch,Joyce;Ucker,DavidS;Levine,JerroldS
• 通讯作者: Levine,JerroldS