Secreted SOCS Proteins as Vectors of Lung Macrophage to Epithelial Cell Crosstalk

 描述(申请人提供)：为了保持体内平衡和正常的气体交换功能，肺必须抑制对感染、抗原和毒素造成的持续攻击的炎症反应。肺远端的宿主反应在很大程度上是由组成肺泡表面的肺泡上皮细胞(AECs)和其常驻免疫细胞肺泡巨噬细胞(AM)之间的相互作用决定的。AM控制AECs炎症反应的机制知之甚少。我们最近发现了一种新的细胞间通讯方式，在这种方式下，AM在膜分隔的小泡中分泌细胞因子信号转导抑制物(SOCS)1和3蛋白，AECs可以在体外和体内利用这些蛋白抑制炎症信号对细胞因子的反应。SoC的AM分泌可以被某些生物活性分子“调节”，包括AECs所阐述的那些分子。此外，吸烟减少，而腺病毒感染增加肺灌洗液中的SOCS水平，这表明SOCS分泌的失调与这些疾病特征的炎症反应的已知变化有关。这项建议旨在更好地了解这种新形式的AM-AEC串扰的基本机制、生物学后果和治疗后果。目的1将描述两种不同类型的囊泡-微粒子和外切体-的释放以及其中SOCS蛋白分泌的调节机制，以响应生物活性分子和AEC衍生因子。目的2将确定这些不同的含SOCs的囊泡在血管内皮细胞中摄取的控制机制，以及跨细胞SOCs输送对靶细胞中细胞因子信号、炎症基因表达、增殖和凋亡的影响。目的3研究吸烟和腺病毒感染所致急性炎症小鼠模型中SOCS分泌失调的作用机制和后果。此外，将在体外和体内测试负载重组SOCS蛋白的合成脂质体囊泡的效果和治疗潜力。这些研究将为肺部炎症的调节提供新的见解，并为控制其的新的治疗方法奠定基础。

 DESCRIPTION (provided by applicant): In order to preserve homeostasis and normal gas exchange function, the lung must restrain inflammatory responses to the continual assault posed by infections, antigens, and toxins. Host responses in the distal lung are dictated in large part by the cross-talk between alveolar epithelial cells (AECs), which comprise the alveolar surface, and alveolar macrophages (AMs), its resident immune cells. Little is known about mechanisms by which AMs control inflammatory responses of AECs. We have recently identified a novel form of intercellular communication in which AMs secrete suppressors of cytokine signaling (SOCS) 1 and 3 proteins within membrane-delimited vesicles that can be taken up by AECs to inhibit inflammatory signaling in response to cytokines in vitro and in vivo. AM secretion of SOCS can be "tuned" by certain bioactive molecules, including those elaborated by AECs. Furthermore, cigarette smoking reduces while adenoviral infection increases SOCS levels in lung lavage fluid, indicating that dysregulation of SOCS secretion is associated with the known alterations in inflammatory responses that characterize these conditions. This proposal seeks to better understand the fundamental mechanisms, biological consequences, and therapeutic ramifications of this novel form of AM-AEC cross-talk. Aim 1 will characterize mechanisms regulating the release of two distinct types of vesicles - microparticles and exosomes - and the secretion of SOCS proteins within them, in response to bioactive molecules as well as AEC-derived factors. Aim 2 will determine the mechanisms controlling uptake of these distinct SOCS-containing vesicles in AECs and the effects of transcellular SOCS delivery on cytokine signaling, inflammatory gene expression, proliferation, and apoptosis in the target cells. Aim 3 will characterize the operative mechanisms for and consequences of dysregulated SOCS secretion in mouse models of acute inflammation induced by cigarette smoking and adenoviral infection. In addition, the effects and therapeutic potential of synthetic liposomal vesicles loaded with recombinant SOCS proteins will be tested in vitro and in vivo. These studies will provide new insights into the regulation of lung inflammation and a foundation for a novel therapeutic approach to its control.