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

 描述（由申请人提供）：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。远端肺中的宿主反应在很大程度上由肺泡上皮细胞（AEC）（其包括肺泡表面）和肺泡巨噬细胞（AM）（其常驻免疫细胞）之间的串扰决定。AM控制AEC炎症反应的机制知之甚少。我们最近已经确定了一种新的形式的细胞间通信，其中AM分泌细胞因子信号转导抑制因子（SOCS）1和3蛋白内的膜界定的囊泡，可以采取由AEC抑制炎症信号在体外和体内细胞因子的反应。AM分泌的SOCS可以通过某些生物活性分子，包括那些精心制作的AEC“调谐”。此外，吸烟减少而腺病毒感染增加肺灌洗液中的SOCS水平，表明SOCS分泌失调与表征这些病症的炎症反应的已知改变相关。该提案旨在更好地了解这种新型AM-AEC串扰的基本机制，生物学后果和治疗后果。目的1将表征调节两种不同类型的囊泡-微粒和外泌体-的释放以及其中SOCS蛋白的分泌的机制，以响应生物活性分子以及AEC衍生因子。目的2将确定这些不同的含SOCS囊泡在AEC中的控制摄取的机制，以及跨细胞SOCS递送对靶细胞中的细胞因子信号传导、炎症基因表达、增殖和凋亡的影响。目的3将描述吸烟和腺病毒感染诱导的小鼠急性炎症模型中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有重组SOCS蛋白的合成脂质体囊泡的作用和治疗潜力。这些研究将为肺部炎症的调节提供新的见解，并为控制炎症的新治疗方法奠定基础。

 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.