Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by excessive ECM deposition and myofibroblast accumulation driven by cytokine dysregulation. This study identified granulocyte colony-stimulating factor 3 (CSF3) as a key mediator of IPF progression. Elevated CSF3 expression was observed in the lung tissues of IPF patients. Recombinant CSF3 promoted myofibrogenesis in lung fibroblasts, whereas CSF3-deficient mice were protected from bleomycin-induced pulmonary fibrosis. Treatment with novel CSF3-neutralizing antibodies significantly restored fibrosis in IPF mice by suppressing myofibroblast differentiation and reducing ECM deposition. Here, we demonstrated a reciprocal regulatory relationship between CSF3 and TGF-β that amplifies pro-fibrotic signaling. Our mechanistic studies revealed that CSF3 acts as an upstream regulator of TGF-β, forming a positive feedback loop that significantly accelerates the fibrotic process. Knockout or neutralization of CSF3 suppressed fibrosis by reducing TGF-β levels, whereas treatment with recombinant CSF3 promoted fibrosis with increased TGF-β expression. Notably, while CSF3 inhibition reduced TGF-β expression levels, it did not decrease them below normal levels. This finding suggests that inhibiting CSF3 could simultaneously reduce fibrosis by suppressing excessive TGF-β expression while also minimizing side effects by maintaining TGF-β homeostasis. Taken together, these results provide strong evidence that CSF3 is a critical driver of IPF pathogenesis and that targeting CSF3 may provide a therapeutic strategy by modulating TGF-β signaling and restoring the ECM and cellular homeostasis.
Kim et al. (Wed,) studied this question.
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