Regulation of inflammation by pulmonary collectins

描述(申请人提供)：在这项资助的延续中，我们建议进一步研究集合素、SP-A和SP-D在幼稚和发炎的肺中所扮演的角色。我们早些时候支持了这样的概念，即这些分子可以作为双重功能的鉴别器，在静息的肺中维持相对抗炎的环境，也可以作为先天免疫系统识别分子，可以启动对损伤和潜在病原体的炎症和免疫反应。这些相反的作用被认为是由于肺集合素头部基团一方面作用于含有ITIM的受体SIRP的抑制作用，另一方面是由于其胶原尾与钙网蛋白和低密度脂蛋白受体相关蛋白(LRP-1)的复合体相互作用而产生的促炎作用。在这次更新中，将在肺巨噬细胞的背景下研究集合素及其候选受体的双重作用。我们假设，常驻肺泡巨噬细胞的表型主要是由其暴露于肺集合素驱动的，肺集素通过SIRP及其下游效应物SHP酪氨酸磷酸酶作用于炎症介质的产生，部分地通过抑制P38 MAPK来维持紧张性抑制刺激。在这个模型中，这些驻留的巨噬细胞的前哨功能表现为它们在应对损伤和入侵时从抑制中解脱出来的能力。我们认为，这种被抑制状态的解锁部分是由于这些相同的集合素现在通过它们的尾巴作用于LRP的相反功能造成的。研究将在体外和幼鼠肺中使用各种潜在的“危险”信号来解决这种平衡问题。这将与在炎症反应过程中迁入肺的“炎性”肺泡巨噬细胞(IAM)形成对比，其明显不同的表型被认为反映了集合素及其对SIRP的刺激作用的减弱。我们进一步建议，并将探索，在炎症反应过程中，驻留的肺泡巨噬细胞持续存在，并在消退后恢复其前哨功能。这些研究将涉及一种系统，在该系统中，小鼠体内的两种巨噬细胞在照射(屏蔽肺部)和移植GFP标记的骨髓后是可区分的。建议炎症巨噬细胞在炎症消退过程中进行局部凋亡和清除，部分原因是肺集合素对它们的保护作用较弱，可能也是通过SIRP发挥作用。与公共卫生相关。正常的肺部经常暴露在外部环境中，需要区分相对无害的暴露和潜在的危险侮辱。驻留的肺泡巨噬细胞被认为是这种区别的重要因素。我们认为，它们通常保持在一种安静的、某种程度上受到抑制的状态，可以通过危险信号释放(解除束缚)，然后启动保护性炎症反应。一种可能的机制是它们对当地肺集合素SP-A和SP-D的反应。本研究的目的是探索SP-A和SP-D的双重功能，它们一方面抑制巨噬细胞的功能，另一方面又能识别外来物质并刺激巨噬细胞产生促炎介质。因此，我们将研究它们对常驻肺泡巨噬细胞独特表型的贡献，最终目的是设计新的介入性方法来调节肺炎性反应及其结果。

DESCRIPTION (provided by applicant): In the continuation of this grant, we propose further examination of the roles played by the collectins, SP-A and SP-D in naive and inflamed lungs. We earlier provided support for the concept that these molecules can act as dual-function discriminators to maintain a relatively anti-inflammatory environment in the resting lung, but also as innate immune system recognition molecules that can initiate inflammation and immune responses to injury and potential pathogens. These opposing effects were proposed to result from the suppressive actions of lung collectin head groups acting on the ITIM-containing receptor, SIRP on the one hand or, in the alternative orientation, pro-inflammatory effects from their collagenous tails interacting with a complex of calreticulin and LDL receptor related protein (LRP-1) on the other. In this renewal, the dual effects of the collectins and their candidate receptors will be pursued in the context of lung macrophages. We hypothesize that the resident alveolar macrophage phenotype is significantly driven by its exposure to the lung collectins, which maintain a tonic suppressive stimulation through SIRP and its downstream effectors, the SHP tyrosine phosphatases acting on inflammatory mediator production through, in part, inhibition of P38 MAPkinase. In this model, the sentinel function of these resident macrophages is represented by their ability to be unshackled from the suppression in response to injury and invasion. We propose that this unshackling of the suppressed state is caused in part by the reversed function of these same collectins now acting through their tails on LRP. Studies will be performed to address this balance using a variety of potential "danger" signals on resident alveolar macrophages (RAM) in vitro and in the naive mouse lung. These will be contrasted with "inflammatory" alveolar macrophages (IAM) that have emigrated into the lung during an inflammatory reaction and whose markedly different phenotype is proposed to reflect a reduced effect of the collectins and their stimulation of SIRP. We further suggest, and will explore, the persistence of resident alveolar macrophages throughout an inflammatory response with return to their sentinel function after resolution. These studies will involve a system in which the two types of macrophage in the mouse are distinguishable following irradiation (with shielding of the lungs) and transplant with GFP-tagged bone marrow. The inflammatory macrophages are suggested to undergo local apoptosis and removal during resolution of the inflammation, in part, because they are less effectively protected from apoptosis by the lung collectins, perhaps also acting through SIRP. PUBLIC HEALTH RELEVANCE. The normal lung is constantly exposed to the external environment and needs to discriminate between relatively harmless exposure and potential dangerous insults. Resident alveolar macrophages are suggested to mediate an important element of this discrimination. We suggest that they are normally maintained in a quiet, somewhat suppressed state that can be released (unshackled) by danger signals to then initiate a protective inflammatory response. A potential mechanism for this is their response to the local lung collectins SP-A and SP-D. The objective of this proposal is to explore the fascinating dual functions of SP-A and SP-D, which in one orientation appear to suppress macrophage function and in another can recognize foreign insults and stimulate the macrophages to produce pro-inflammatory mediators. Accordingly we will examine their contribution to the unique phenotype of the resident alveolar macrophage with an ultimate objective of devising new interventional approaches to regulate pulmonary inflammatory reactions and their outcomes.