Fibroblast EGFR signaling mediates ricin toxin-induced acute lung injury via EGR1/CXCL1 axis.

Ricin toxin (RT), a highly potent plant-derived toxin, represents a critical threat due to its capacity to induce fatal acute lung injury (ALI) upon inhalation. While the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase predominantly expressed on epithelial cells and fibroblasts, regulates cellular processes such as growth, proliferation, differentiation and inflammation, its involvement in RT-induced ALI remains unexplored. This study investigates this relationship using a mouse model of ALI induced by aerosolized RT at a dose of 2.0 × LD (approximately 0.01 mg kg ). The results demonstrate that damage to alveolar epithelial type II (AT2) cells leads to the release of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which activates EGFR on fibroblasts, exacerbating lung injury pathology and reducing survival. Mechanistically, EGFR activation in fibroblasts induces the early growth response protein 1 (EGR1), which subsequently enhances chemokine C-X-C motif ligand 1 (CXCL1) secretion 24 h post-exposure, promoting neutrophil infiltration in the lung. RNA sequencing analysis corroborates these findings. Notably, pharmacological inhibition of EGFR phosphorylation using Erlotinib (ERL) significantly mitigates the inflammatory response in RT-induced ALI. These results not only illuminate the immune response in lung tissue but also highlight EGFR signaling in fibroblasts as a pivotal mediator of RT-induced ALI. This study identifies a novel therapeutic strategy targeting EGFR signaling in fibroblasts for the treatment of inflammatory lung diseases.