Mechanisms of pulmonary landscape remodelling during resolution of inflammation

免疫细胞清除细菌病原体是维持器官内环境稳定的关键。尽管如此，必须控制和限制这种炎症反应，以防止组织损伤。在肺部，血小板积极参与细菌引发的肺部炎症的发生和消退。未消退的炎症与器官纤维化和肺内长期器官功能受损有关。肺纤维化最近被描述为依赖于特定的巨噬细胞亚群，但它们参与细菌引发的炎症模型仍不清楚。我们的研究小组先前已经证实，在肺部炎症缓解过程中，血小板影响肺泡巨噬细胞，但到目前为止，血小板对肺间质景观的影响尚不清楚。为了明确血小板对肺景观重组的影响，我们现在将详细分析肺间质中血小板依赖的巨噬细胞表型转换的分子机制。此外，我们还将研究巨噬细胞和T细胞亚群在肺部细菌感染后器官纤维化中的作用。最后，为了理解我们工作的翻译方面，我们将评估人类炎症和消退过程中肺血小板和巨噬细胞的存在和参与。使用从获得的数据中获得的翻译遗传基因敲除模型，然后我们将证明疾病的相关性和可能的治疗意义。因此，这项提议包括三个中心目标，我们将在其中进行研究：1)细菌感染后肺间质巨噬细胞景观的变化及其功能后果。2)间质巨噬细胞亚群的来源、存在和表型启动通过间接和直接的血小板依赖过程。3)人ARDS患者炎症和消退过程中血小板和巨噬细胞的存在、细胞相互作用和参与。

Clearance of bacterial pathogens by immune cells is crucially needed to maintain organ homeostasis. Nonetheless, such inflammatory reaction must be controlled and limited to prevent tissue damage. In the lung, platelets actively participate in both the onset and the resolution of bacterially triggered pulmonary inflammation. Non-resolving inflammation is linked to organ fibrosis and impaired long-term organ function in the lung. Lung fibrosis has recently been described to rely on specific macrophage subsets, but their involvement in models of bacterially triggered inflammation remains unclear. Our group could previously demonstrate that platelets affect alveolar macrophages during resolution of pulmonary inflammation, but impact of platelets on pulmonary interstitial landscape is so far unclear. To define the impact of platelets on pulmonary landscape recomposition, we will now analyze in detail the molecular mechanisms of platelet-dependent macrophage-phenotype switches in lung interstitium. In addition, we will investigate the impact of macrophage and T-cell subsets on organ fibrosis following bacterial infections of the lung. Finally, to understand translational aspects of our work, we will assess presence and involvement of pulmonary platelets and macrophages during inflammation and resolution in humans. Using translational genetic knockout models derived from the obtained data, we will then demonstrate the disease relevance and possible therapeutic implications. This proposal therefore consists of three central aims in which we will investigate: 1) Changes of the pulmonary interstitial macrophage landscape following bacterial infection and functional consequences of such. 2) The origin, presence and phenotypic priming of distinct pro- and anti-resolution interstitial macrophage subsets by indirect and direct platelet-dependent processes. 3) Presence, cellular interplay and involvement of platelets and macrophages during inflammation and resolution in human ARDS patients.