IL-1β Induces a Pro-Inflammatory Fibroblast Microenvironment that Impairs Lung Progenitors' Function.

Chronic Obstructive Pulmonary Disease (COPD) is characterized by a persistent inflammatory state in the lungs and defective tissue repair. While the inflammatory response in COPD patients 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 elevated 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. While direct treatment of the lung organoids with IL-1β promoted organoids growth, this switched towards inhibition when added as fibroblasts' pre-treatment followed by organoids treatment. We then investigated the IL-1β-driven mechanisms in the fibroblasts and found an inflammatory response related to CXCL chemokines; we confirmed that these chemokines were responsible for the impaired organoids growth and found that targeting their CXCR1/2 receptors or the IL-1β intracellular signaling reduced the pro-inflammatory response and restored organoids growth. These data demonstrate that IL-1β alters the fibroblasts' state by promoting a distinct inflammatory response, switching their supportive function on epithelial progenitors towards an inhibitory one in an organoid assay. These results imply that chronic inflammation functions as a shift towards inhibition of repair, thereby contributing to chronic inflammatory diseases like COPD.