IL-1β诱导促炎性成纤维细胞微环境，损害肺前体细胞功能

IL-1β Induces a Proinflammatory Fibroblast Microenvironment that Impairs Lung Progenitors' Function

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY

影响因子:5.3

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

DOI: 10.1165/rcmb.2022-0209OC

摘要

慢性阻塞性肺疾病（COPD）以肺部持续性炎症状态和组织修复障碍为特征。尽管COPD患者的炎症反应已被充分研究，并在发作期表现出过度反应，但其对肺损伤和异常修复的具体贡献仍不清楚。本研究旨在探讨炎症微环境如何影响参与远端肺组织修复的上皮前体细胞及其支持的间充质微环境细胞。我们重点关注在COPD发作期间升高的IL-1β，一种关键的炎症介质，并采用肺上皮细胞和成纤维细胞的类器官模型评估IL-1β对这些细胞转录组和分泌因子的影响。结果显示，直接用IL-1β处理肺类器官促进其生长，但当用成纤维细胞预处理后再处理类器官时，生长则受到抑制。随后，我们研究了IL-1β在成纤维细胞中的作用机制，发现其引起与(C-X-C基序)趋化因子（CXCL）相关的炎症反应；证实这些趋化因子是损害类器官生长的原因，并发现靶向它们的C-X-C趋化因子受体1/2（CXCR1/2）或抑制IL-1β的细胞内信号传导可以减轻促炎反应并恢复类器官生长。这些数据表明，IL-1β通过促进特定的炎症反应改变成纤维细胞状态，将其对上皮前体细胞的支持功能转变为抑制性。这些结果暗示，慢性炎症可能作为一种抑制修复的机制，促使像COPD这样的慢性炎症性疾病的发生。

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.