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

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Inflammation Research

Background:

• Chronic obstructive pulmonary disease (COPD) features persistent lung inflammation and impaired tissue repair.
• The precise role of the inflammatory microenvironment in COPD-related lung injury and abnormal repair remains incompletely understood.

Purpose of the Study:

• To investigate how the inflammatory microenvironment, specifically Interleukin-1 beta (IL-1β), impacts lung epithelial progenitors and mesenchymal niche cells crucial for distal lung repair.
• To elucidate the mechanisms by which IL-1β influences fibroblast function and its subsequent effect on epithelial repair in a lung organoid model.

Main Methods:

• Utilized a lung organoid model comprising lung epithelial cells and fibroblasts.
• Assessed the effects of IL-1β treatment on organoid growth, transcriptome, and secreted factors.
• Investigated IL-1β-driven mechanisms in fibroblasts, focusing on chemokine signaling (CXCL) and their receptors (CXCR1/2).

Main Results:

• Direct IL-1β treatment initially promoted organoid growth, but pretreatment of fibroblasts with IL-1β inhibited subsequent organoid growth.
• IL-1β induced an inflammatory response in fibroblasts involving CXCL chemokines, which were responsible for impaired organoid growth.
• Targeting CXCR1/2 receptors or IL-1β intracellular signaling reversed the inhibitory effect and restored organoid growth.

Conclusions:

• IL-1β alters fibroblast phenotype, shifting their supportive role for epithelial progenitors to an inhibitory one within the lung microenvironment.
• These findings suggest that chronic inflammation in COPD contributes to disease progression by inhibiting tissue repair mechanisms.
• Modulating fibroblast inflammatory responses presents a potential therapeutic strategy for improving tissue repair in chronic inflammatory lung diseases.