IL-1β诱导促炎的成纤维细胞微环境，损害肺祖细胞的功能
IL-1β Induces a Proinflammatory Fibroblast Microenvironment that Impairs Lung Progenitors' Function
影响因子:5.30000
分区:医学2区 / 生化与分子生物学2区 细胞生物学2区 呼吸系统2区
发表日期:2023 Apr
作者:
Chiara Ciminieri, Manon E Woest, Niki L Reynaert, Irene H Heijink, René Wardenaar, Diana C J Spierings, Corry-Anke Brandsma, Melanie Königshoff, Reinoud Gosens
摘要
慢性阻塞性肺疾病（COPD）的特征是肺部持续的炎症状态和组织不良。尽管COPD患者的炎症反应被很好地表征，并且已知在加重过程中被夸大，但其对肺损伤和异常修复的贡献尚不清楚。在这项研究中，我们旨在研究炎症微环境如何影响上皮祖细胞及其支持的间充质细胞，其中涉及远端肺组织的组织修复。我们专注于IL-1β，这是一种在COPD加重期间增加的关键炎症介质，并使用了肺上皮细胞的器官模型和成纤维细胞来评估IL-1β处理对这些细胞转录组和分泌因素的影响。尽管用IL-1β直接治疗肺类器官促进了器官生长，但当将其添加为成纤维细胞预处理后，然后进行器官治疗时，这切换到了抑制作用。然后，我们研究了成纤维细胞中IL-1β驱动的机制，并发现与（C-X-C基序）配体（CXCL）趋化因子相关的炎症反应；我们证实，这些趋化因子是导致器官生长受损的原因，发现针对其C-X-C趋化因子受体1/2（CXCR1/2）受体或IL-1β细胞内信号传导降低了促炎反应并恢复器官生长。这些数据表明，IL-1β通过促进明显的炎症反应来改变成纤维细胞的状态，从而将其对上皮祖细胞的支持功能转换为在器官测定中的抑制作用。这些结果表明，慢性炎症起着抑制修复的转变，从而导致慢性炎症性疾病等慢性炎症性疾病。
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by a persistent inflammatory state in the lungs and defective tissue repair. Although the inflammatory response in patients with COPD is well characterized and known to be exaggerated during exacerbations, its contribution to lung injury and abnormal repair is still unclear. In this study, we aimed to investigate how the inflammatory microenvironment affects the epithelial progenitors and their supporting mesenchymal niche cells involved in tissue repair of the distal lung. We focused on IL-1β, a key inflammatory mediator that is increased during exacerbations of COPD, and used an organoid model of lung epithelial cells and fibroblasts to assess the effect of IL-1β treatment on these cells' transcriptome and secreted factors. Whereas direct treatment of the lung organoids with IL-1β promoted organoid growth, this switched toward inhibition when it was added as fibroblast pretreatment followed by organoid treatment. We then investigated the IL-1β-driven mechanisms in the fibroblasts and found an inflammatory response related to (C-X-C motif) ligand (CXCL) chemokines; we confirmed that these chemokines were responsible for the impaired organoid growth and found that targeting their C-X-C chemokine receptors 1/2 (CXCR1/2) receptors or the IL-1β intracellular signaling reduced the proinflammatory response and restored organoid growth. These data demonstrate that IL-1β alters the fibroblasts' state by promoting a distinct inflammatory response, switching their supportive function on epithelial progenitors toward an inhibitory one in an organoid assay. These results imply that chronic inflammation functions as a shift toward inhibition of repair, thereby contributing to chronic inflammatory diseases like COPD.