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性免疫应答的矛盾变化。许多个体的炎症状态随着年龄的增长显著增加，即使在没有明显感染的情况下，调节这些反应的能力减弱，这与多种衰老相关疾病的发病机制有因果关系，并且可能主要涉及衰老相关免疫功能障碍的所有方面。我们试图了解这些与年龄相关的免疫反应性有害变化的原因。我们最近的研究强调了巨噬细胞和其他吞噬细胞清除死细胞的显著和深刻的炎症和免疫后果。特异性凋亡细胞识别的过程代表了一种普遍存在的和非常规的先天免疫，其区分衰竭细胞和活细胞，并有效地调节炎症。凋亡尸体的调节活性，代表生理性细胞死亡过程中获得的功能获得，表现为响应细胞内促炎细胞因子基因转录的立即早期抑制，并在结合时发挥作用，与随后的吞噬无关。我们的新数据表明，这种先天免疫反应性显着老化相关的下降。值得注意的是，这种衰老相关效应反映了凋亡调节的定量而非绝对改变。我们推测，衰老相关的减少，在免疫调节所施加的凋亡细胞可能是基础和加剧的矛盾和病理变化的免疫衰老。这项建议中概述的工作集中在先天性凋亡识别和反应中与衰老相关的改变的机制表征上。我们将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的能力，从而以衰老相关的方式改变其炎症反应的信号和调节，采用反映这种特定反应途径的各种功能分子标准。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。对凋亡细胞生理性免疫调节过程的更全面了解，对于干预导致和加剧免疫衰老的有害和病理性炎症反应的病例具有巨大意义。公共卫生相关性：细胞在生物体的整个生命过程中正常死亡，并且那些死亡的（“凋亡”）细胞被吞噬细胞识别并清除。我们发现，死亡细胞发挥有效的抗炎和其他影响的吞噬细胞，识别他们，通过一个特征的信号事件库。我们还发现，随着年龄的增长，对死亡细胞的反应性降低，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其作用的调节机制，并研究在这一反应途径中与衰老相关的缺陷的分子本质。这些研究将揭示炎症调节的新方面。更深入地了解凋亡细胞在生理上施加的炎症（和免疫）调节以及所涉及的分子事件可能会揭示炎症控制的新靶点，这对于干预病理性炎症（包括导致和加剧免疫衰老的炎症反应）具有巨大潜力。

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.