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Unveiling the molecular mechanisms of tissue remodelling following injury is imperative to elucidate its regenerative capacity and aberrant repair in disease. Using different omics approaches, we identified enhancer of zester homolog 2 (EZH2) as a key regulator of fibrosis in injured lung epithelium. Epithelial injury drives an enrichment of nuclear transforming growth factor‐β‐activated kinase 1 (TAK1) that mediates EZH2 phosphorylation to facilitate its liberation from polycomb repressive complex 2 (PRC2). This process results in the establishment of a transcriptional complex of EZH2, RNA‐polymerase II (POL2) and nuclear actin, which orchestrates aberrant epithelial repair programmes. The liberation of EZH2 from PRC2 is accompanied by an EZH2‐EZH1 switch to preserve H3K27me3 deposition at non‐target genes. Loss of epithelial TAK1, EZH2 or blocking nuclear actin influx attenuates the fibrotic cascade and restores respiratory homeostasis. Accordingly, EZH2 inhibition significantly improves outcomes in a pulmonary fibrosis mouse model. Our results reveal an important non‐canonical function of EZH2, paving the way for new therapeutic interventions in fibrotic lung diseases., TAK1‐mediated phosphorylation of EZH2 regulates fibrotic epithelial remodelling after injury. EZH2 inhibition improves outcomes in a pulmonary fibrosis model, suggesting that targeting the TAK1‐EZH2 axis has therapeutic efficacy for idiopathic pulmonary fibrosis (IPF).

Smoking is an important risk factor for the development of chronic obstructive pulmonary disease (COPD) and viral infections are believed to be major triggers of exacerbations, which periodically lead to a worsening of symptoms. The pro-inflammatory IL-1 family members IL-1α and IL-1β are increased in COPD patients and might contribute to disease pathology. We investigated whether individual or combined inhibition of these cytokines reduced lung inflammation in cigarette smoke (CS)-exposed and H1N1-infected BALB/c mice. Animals were treated with individual or combined antibodies (Abs) directed against IL-1α, IL-1β or IL-1R1. Cells in BAL fluid and cytokines/chemokines in lung homogenate were determined. The viral load was investigated. Blocking IL-1α had significant suppressive effects on total cells, neutrophils, and macrophages. Furthermore, it reduced KC levels significantly. Blocking of IL-1β did not provide significant activity. In primary human bronchial epithelial air-liquid-interface cell cultures infected with H1N1, IL-1α Abs but not IL-1β Abs reduced levels of TNF-α and IL-6. Concomitant usage of Abs against IL-1α/IL-1β revealed strong effects in vivo and reduced total cells, neutrophils and macrophages. Additionally, levels of KC, IL-6, TNF-α, MCP-1, MIP-1α and MIP-1β were significantly reduced and ICAM-1 and MUC5 A/C mRNA expression was attenuated. The viral load decreased significantly upon combined IL-1α/IL-1β Ab treatment. Blocking the IL-1R1 provided significant effects on total cells, neutrophils and macrophages but was inferior compared to inhibiting both its soluble ligands IL-1α/IL-1β. Our results suggest that combined inhibition of IL-1α/IL-1β might be beneficial to reduce CS/H1N1-induced airway inflammation. Moreover, combined targeting of both IL-1α/IL-1β might be more efficient compared to individual neutralization IL-1α or IL-1β or inhibition of the IL-1R1.

Background: Smoking is an important risk factor for the development of chronic obstructive pulmonary disease (COPD) and viral infections are believed to be an important trigger of exacerbations. IL-1α, IL-1β and IL-18 are increased in COPD patients and may contribute to disease pathology. Aims and Objectives: To investigate if the individual inhibition of IL-1α, IL-1β, IL-18, the combined inhibition of IL-1β/IL-18, or the antagonisation of IL-1RI reduces inflammation in cigarette-smoke (CS) exposed mice or in CS/influenza treated mice. Methods: Mice were either exposed to CS only or additionally infected with influenza. The animals were treated with antibodies directed against IL-1α, IL-1β or IL-18 or with antibodies antagonising IL-1RI. Cells, cytokines and chemokines in BAL fluid and lung homogenate were determined. Results: IL-1α neutralisation or antagonisation of IL-1RI significantly reduced KC, IL-6 and neutrophils in CS and CS/influenza treated mice. In contrast, IL-1β neutralisation failed to reduce these parameters. IL-18 neutralising antibodies had no effect in CS exposed mice but reduced neutrophils significantly in the CS/influenza treated mice. Simultanous neutralisation of both IL-1β/IL-18 had no substantial effect in the CS exposed mice but exerted additive effects in the CS/influenza treated mice and reduced IL-6 and neutrophils significantly. Conclusions: These results suggest that inhibition of IL-1α, the combined inhibition of IL-1β and IL-18, or the antagonisation of IL-1RI may reduce inflammation and exacerbations in COPD patients.