Aging and Apoptotic Modulation of Immune Responsiveness

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，调节这些反应的能力减弱也与各种衰老相关疾病的发病机制有关，并可能集中参与衰老相关免疫功能障碍的方方面面。我们试图了解这些与年龄相关的、有害的免疫反应改变的原因。我们最近的研究强调了巨噬细胞和其他吞噬细胞清除死亡细胞所产生的显著而深刻的炎症和免疫学后果。特定的凋亡细胞识别过程代表了一种无处不在的、非常规的先天免疫，它区分衰弱的细胞和存活的细胞，并有效地调节炎症。凋亡身体的调节活性代表着在生理性细胞死亡过程中获得的功能获得，表现为立即早期抑制反应细胞内的促炎细胞因子基因转录，并在结合时发挥作用，而不是随后的吞噬。我们的新数据表明，这种与生俱来的免疫反应性随着年龄的增长而显著下降。值得注意的是，这种与衰老相关的效应反映了细胞凋亡调控的数量变化，而不是绝对变化。我们推测，衰老相关的免疫调节功能的减弱可能是免疫衰老的矛盾和病理改变的基础，并可能加剧免疫衰老。这项提案中概述的工作集中在与生俱来的细胞凋亡识别和反应中与衰老相关的变化的机制表征。我们将采用反映这一特定反应途径的各种功能分子标准，直接评估巨噬细胞和其他专业和非专业吞噬细胞与凋亡细胞相互作用并吞噬凋亡细胞从而发出信号并调节其炎症反应的能力是否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。与公共健康相关：细胞在生物体的整个生命周期中正常死亡，那些死亡的(“凋亡”)细胞被吞噬细胞识别并清除。我们发现，死亡细胞通过一系列特有的信号事件，在识别它们的吞噬细胞上发挥强大的抗炎和其他作用。我们还发现，随着年龄的增长，对死亡细胞的反应性会降低，我们假设这可能与衰老相关的免疫失调(免疫衰老)引起的病理学有关。我们将研究死亡细胞发挥作用的调控机制，并研究这一反应途径中与衰老相关的缺陷的分子性质。这些研究将揭示炎症调控的新方面。深入了解细胞凋亡在生理上对炎症(和免疫)的调节作用以及所涉及的分子事件，可能会揭示炎症控制的新靶点，对于病理性炎症的干预具有巨大的潜力，包括作为免疫衰老基础和加剧的炎症反应。

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. We seek to understand the causes of these age-related and deleterious alterations in immune responsiveness. Our recent studies have highlighted the remarkable and profound inflammatory and immunological consequences of the clearance of dead cells accomplished by macrophages and other phagocytic cells. The process of specific apoptotic cell recognition represents a ubiquitous and unconventional innate immunity that discriminates effete from viable cells and that potently modulates inflammation. 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 responding cell, and is exerted upon binding, independent of subsequent engulfment. Our new data demonstrate a striking aging-associated decline in this innate immune responsiveness. Significantly, this aging-associated effect reflects a quantitative, and not an absolute, alteration in apoptotic modulation. We hypothesize that the aging-associated diminution in immune modulation exerted by apoptotic cells may underlie and exacerbate the paradoxical and pathological alterations of immunosenescence. The work outlined in this proposal focuses on the mechanistic characterization of the aging-associated alterations in innate apoptotic recognition and response. We will evaluate directly whether the abilities of macrophages and other professional and non-professional phagocytes to interact with and engulf apoptotic cells and consequently to signal and modulate their inflammatory responses are altered in an aging-associated manner, employing a variety of functional molecular criteria reflective of this specific response pathway. 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. PUBLIC HEALTH RELEVANCE: Cells die normally throughout the life of an organism, and those dead ("apoptotic") cells are recognized by phagocytes and cleared. We find that dead cells exert potent anti-inflammatory and other effects on the phagocytes that recognize them, exerted through a characteristic repertoire of signaling events. We also find that responsiveness to dead cells is diminished with increasing age, and we hypothesize that this may be casually linked to the pathologies that arise as a consequence of aging-associated immune dysregulation ("immunosenescence"). We will study the regulatory mechanism by which dead cells exert their effects, and examine the molecular nature of aging-associated defects in this response pathway. These studies will reveal new aspects of inflammatory regulation. A deeper understanding of the inflammatory (and immune) modulation exerted physiologically by apoptotic cells and of the molecular events involved may reveal new targets for inflammatory control, with great potential for intervention in cases of pathological inflammation, including inflammatory responses that underlie and exacerbate immunosenescence.