Integrin-dependent modulation of macrophage function

 描述(申请人提供)：组织居留巨噬细胞(Mφ)是先天免疫系统的第一道防线和关键的细胞室之一，具有特殊的感觉、内稳态和效应器功能，使宿主能够保护免受入侵病原体的侵袭，并对组织损伤或压力做出足够的反应。如果Mφ中的动态平衡信号通路被破坏，组织中的Mφ可能参与了病理过程，目前认为绝大多数人类急慢性疾病的发生与来自Mφ隔室的致病因子有关。通过对体内转录反应和坏死细胞死亡的分析，我们做出了初步的观察，尽管血液中的病毒和细菌病原体被有效捕获，但肝和脾中的MφS利用不同的分子机制来执行坏死和激活促炎介质。此外，我们偶然地发现，在体外和体内操纵β-1整合素在M-φ上的表达显著改变了其抗病原体和促炎反应的表型。由于组织MφS的表型异质性是最近才显现出来的，而且现在是该领域的一个密集研究主题，目前关于在表型和功能水平上驱动这种异质性的一般分子机制的信息很少。这项拨款提案的主要目标是评估整合素作为细胞外信号传感器的概念，并指导MφS对组织微环境的功能承诺，并确定使Mβ1整合素依赖的功能专门化对于平衡动态平衡和/或保护性宿主对病毒和细菌病原体的反应至关重要的分子机制和信号通路(S)。因此，在特定的目标1中，我们将定义分子机制和信号通路，使β1整合素依赖于在体外对促炎Mφ反应的调节。在特定的目标2中，我们将确定β1整合素在体内对肝和脾MφS功能特化的指导作用。在具体目标3中，我们将定义β1的角色 整合素在指导胚胎和成人单核细胞来源的M-φ体内组织承诺表型中的作用。这项拟议的研究将为体内与促炎M-φ反应相关的基本细胞和分子生物学过程提供新的机制见解，并将有助于识别新的潜在治疗靶点。 无根据的严重和/或病理性炎症。

 DESCRIPTION (provided by applicant): Tissue residential macrophages (Mφ) are the first line of defense and one of the key cellular compartments of the innate immune system with specialized sensory, homeostatic, and effector functions that enable host protection from invading pathogens and mount adequate response to tissue damage or stress. If homeostatic signaling pathways in Mφ become dis-regulated, tissue Mφ may contribute to pathology and it is currently believed that the vast majority of human acute and chronic diseases develop with significant contributions from pro-pathogenic factors derived from the Mφ compartment. Through analyzing transcriptional responses and necrotic cell death in vivo, we have made an original observation that despite the efficient trapping of viral and bacterial pathogens from the blood, resident Mφs in liver and spleen utilize distinct molecular machineries to execute necrosis and activate pro-inflammatory mediators. Furthermore, we serendipitously found that manipulation of β1 integrin expression on Mφ in vitro and in vivo drastically alters their anti-pathogen and pro-inflammatory response phenotypes. Because the phenotypic heterogeneity of tissue Mφs became evident only recently and now is a topic of intense research in the field, littl to no information is currently available on generalized molecular mechanisms that drive this heterogeneity both at phenotypic and functional levels. The major goals of this grant proposal are to evaluate the concept that integrins serve as sensors of extracellular cues and guide the functional commitment of Mφs to tissue microenvironments and to define the molecular mechanism and signaling pathway(s) that enable β1 integrin dependent functional specialization of Mφs that is critical for balanced homeostatic and/or protective host responses to viral and bacterial pathogens. Therefore, in Specific Aim 1, we will define molecular mechanisms and signaling pathways that enable β1 integrin-dependent modulation of pro-inflammatory Mφ responses in vitro. In Specific Aim 2, we will define the role of β1 integrin in guiding functiona specialization of liver and splenic Mφs in vivo. In Specific Aim 3, we will define the role of β1 integrin in guiding tissue commitment phenotypes of embryonically-derived and adult monocyte-derived Mφs in vivo. The proposed studies will provide new mechanistic insights into fundamental cellular and molecular biological processes related to pro- inflammatory Mφ responses in vivo, and will allow for identification of novel potential therapeutic targets to tame unwarranted severe and/or pathologic inflammation.