The immunomodulatory effects of extracellular Hsp70

细胞外Hsp70的免疫调节作用

• 批准号: 7084364
• 负责人: DEREK S WHEELER
• 金额: $ 12.1万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7084364
• 关键词: cytokine; cytoprotection; genetically modified animals; gram positive bacteria; heat shock proteins; immunomodulators; inflammation; laboratory mouse; lipopolysaccharides; macrophage; monocyte; nuclear factor kappa beta; septicemia; stress

DESCRIPTION (provided by applicant): During steady-state conditions, heat shock proteins (HSPs) function in the intracellular compartment as molecular chaperones, assisting with the assembly, stabilization, folding, and transport of proteins. Under conditions of stress, HSPs bind and stabilize misfolded proteins and protect them from denaturation, thereby conferring resistance to further stress, an effect known as "stress tolerance." Recent evidence has focused attention on the role that extracellular HSPs play in the host innate immune response as opposed to their more commonly ascribed intracellular chaperone functions. For example, extracellular Hsp70, a member of the 70 kDa family of HSPs plays an important immuno-modulatory role, serving as both a chaperone and cytokine ("chaperokine"). This new paradigm may be explained by the so-called "danger hypothesis", in which stressed cells release Hsp70 into their surrounding extracellular milieu to signal an impending "danger" to neighboring cells. We have shown that stressed monocytes and macrophages release functional Hsp70 in vitro and that extracellular Hsp70 correlates with poor outcome in children with septic shock. Several questions, however, remain unanswered. Our goals are to further elucidate the mechanisms leading to the extracellular release of Hsp70 and to understand the functional role of extracellular Hsp70 in vitro and in vivo. Accordingly, the central hypothesis of the current proposal is that extracellular Hsp70 modulates important proinflammatory signal transduction pathways in vitro and in vivo. Using a variety of techniques and models, we will determine the conditions and mechanisms leading to release of Hsp70 in vitro and in vivo (Specific Aim 1), determine the effect of extracellular Hsp70 on the innate immune response to components of both gram negative and gram positive bacteria in vitro and in vivo (Specific Aims 2, 3), and determine the effects of extracellular Hsp70 on the innate immune response to polymicrobial sepsis in vivo (Specific Aim 4). The novel finding that an endogenous molecule such as Hsp70 could modulate the host response to a variety of stimuli acting via multiple receptor pathways would provide important insight regarding the functional role of extracellular HSP70 and could ultimately provide a mechanistic link between tissue injury and modulation of the host innate immune response in clinical conditions such as trauma, sepsis, and MODS.

描述（由申请人提供）：在稳态条件下，细胞内室中的热休克蛋白（HSP）作为分子伴侣，有助于组装，稳定，折叠和蛋白质的运输。在压力条件下，HSP结合并稳定错误折叠的蛋白质并保护其免受变性，从而赋予对进一步应激的抗性，这种效果称为“胁迫耐受性”。最近的证据将注意力集中在细胞外HSP在宿主先天免疫反应中发挥的作用，而不是其常见的细胞内伴侣功能。例如，70 kDa HSP家族的成员细胞外HSP70起重要的免疫调节作用，既是伴侣蛋白和细胞因子（“伴侣”）。这种新的范式可以用所谓的“危险假说”来解释，其中应力细胞将HSP70释放到其周围的细胞外环境中，以表明对邻近细胞的“危险”。我们已经表明，压力的单核细胞和巨噬细胞在体外释放功能性HSP70，并且细胞外HSP70与败血性休克儿童的预后不良相关。但是，几个问题仍未得到答复。我们的目标是进一步阐明导致HSP70细胞外释放的机制，并了解细胞外HSP70体外和体内的功能作用。因此，当前建议的中心假设是细胞外HSP70在体外和体内调节重要的促炎信号转导途径。使用多种技术和模型，我们将确定导致Hsp70在体内释放HSP70的条件和机制（具体目标1），确定细胞内HSP70对革兰氏阴性和革兰氏阳性细菌在体外和gram sypteria intss in Baster and inter intsss in Better and Sps sps Sps的影响2，3）的影响（3），并确定对2，3）的影响（3），并确定2，3）的影响（3）体内多数败血症（特定目标4）。这一新发现，即HSP70等内源分子可以通过多种受体途径调节对各种刺激作用的宿主反应，这将提供有关细胞外HSP70功能作用的重要见解，并最终可以在诸如Trauma，Sepis和Mods之类的临床情况下提供组织损伤与宿主先天免疫反应的组织损伤之间的机械联系。