IGF1R deficiency mitigates acute lung injury by promoting anti-inflammatory transcriptional profiles.
BACKGROUND: Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and COVID-19 are characterized by hyperinflammation, commonly referred to as "cytokine storm". The insulin-like growth factor (IGF) pathway, particularly the type 1 receptor (IGF1R), plays a critical role in lung homeostasis and has been implicated in the pathogenesis of pulmonary inflammatory diseases. In mice, widespread Igf1r deficiency attenuates lung inflammation and alveolar damage in bleomycin (BLM)-induced ALI. METHODS: We analyzed single-cell RNA sequencing datasets from lung tissue of COVID-19 cases and control donors as well as mouse lungs to determine Igf1r and IGF family expression across pulmonary cell types. Furthermore, we conducted bulk RNA sequencing on lungs from Igf1r-deficient mice three days after BLM or saline instillation, followed by differential expression and functional enrichment analyses. Findings were further tested through protein detection, assessment of DNA damage and methylation in lung tissues, and functional assays using Igf1r-deficient primary mouse embryonic fibroblasts (MEFs). RESULTS: IGF1R was broadly expressed across multiple cell types in both human and mouse lungs under normal and pathological conditions. Other IGF family members showed cell-type-specific expression, which was modulated by lung injury. Transcriptomic profiling revealed differentially expressed genes between BLM-challenged and control mouse lungs, detecting biological processes and signaling pathways involved in ALI pathobiology. Igf1r deficiency in BLM-challenged mice reversed a large fraction of the transcriptional changes triggered by BLM, including "cytokine storm"-related gene expression. Functional enrichment analysis additionally revealed significant modulation of pathways related to DNA damage, metabolic reprogramming, mitochondrial homeostasis, and epigenetic regulation. In vitro, Igf1r-deficient MEFs exhibited decreased mitochondrial respiration and glycolysis, protection against BLM-induced nuclear damage and mitochondrial accumulation, and decreased histone H3 acetylation. Moreover, Igf1r-deficient mouse lungs displayed increased global DNA methylation following BLM challenge. CONCLUSIONS: IGF1R is a key modulator of the inflammatory and molecular response to ALI pathogenesis. IGF1R deficiency dampens the "cytokine storm", modifies transcriptional and epigenetic profiles and promotes protective cellular responses. These findings highlight IGF1R signaling as a potential therapeutic target in ARDS and related lung injuries.