Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH; and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH.
J Immunol. 2023 Mar 15;210(6):832-841. doi: 10.4049/jimmunol.2200511.
Fibrosis is characterized by inappropriately persistent myofibroblast accumulation and excessive extracellular matrix deposition with the disruption of tissue architecture and organ dysfunction. Regulated death of reparative mesenchymal cells is critical for normal wound repair, but profibrotic signaling promotes myofibroblast resistance to apoptotic stimuli. A complex interplay between immune cells and structural cells underlies lung fibrogenesis. However, there is a paucity of knowledge on how these cell populations interact to orchestrate physiologic and pathologic repair of the injured lung. In this context, gasdermin-D (GsdmD) is a cytoplasmic protein that is activated following cleavage by inflammatory caspases and induces regulated cell death by forming pores in cell membranes. This study was undertaken to evaluate the impact of human (Thp-1) monocyte-derived extracellular vesicles and GsdmD on human lung fibroblast death. Our data show that active GsdmD delivered by monocyte-derived extracellular vesicles induces caspase-independent fibroblast and myofibroblast death. This cell death was partly mediated by GsdmD-independent induction of cellular inhibitor of apoptosis 2 (cIAP-2) in the recipient fibroblast population. Our findings, to our knowledge, define a novel paradigm by which inflammatory monocytes may orchestrate the death of mesenchymal cells in physiologic wound healing, illustrating the potential to leverage this mechanism to eliminate mesenchymal cells and facilitate the resolution of fibrotic repair.
纤维化的特征是不适当的持续肌成纤维细胞积累和细胞外基质的过度沉积，导致组织架构的破坏和器官功能障碍。修复性间充质细胞的程序性死亡对于正常的伤口修复至关重要，但成纤维信号促进肌成纤维细胞对凋亡刺激的抵抗。免疫细胞和结构细胞之间的复杂相互作用是肺纤维化发生的基础。然而，对于这些细胞群体如何相互作用以协调受损肺的生理和病理修复，我们的了解还很匮乏。在这种情况下，gasdermin-D（GsdmD）是一种细胞质蛋白，在炎症半胱天冬酶切割后被激活，并通过在细胞膜上形成孔来诱导细胞的程序性死亡。本研究旨在评估人（Thp-1）单核细胞衍生的细胞外囊泡和 GsdmD 对人肺成纤维细胞死亡的影响。我们的数据表明，单核细胞衍生的细胞外囊泡传递的活性 GsdmD 诱导 caspase 非依赖性成纤维细胞和肌成纤维细胞死亡。这种细胞死亡部分是通过受体成纤维细胞群体中细胞凋亡抑制剂 2（cIAP-2）的 GsdmD 非依赖性诱导介导的。据我们所知，我们的发现定义了一个新的范式，即炎症单核细胞可以协调间充质细胞在生理伤口愈合中的死亡，这表明利用这种机制消除间充质细胞并促进纤维化修复的解决是可能的。
