Transcriptomics of acute injured lungs reveals IGF1R action on DNA damage response, metabolic reprogramming, mitochondrial homeostasis and epigenetics

Abstract Background. Acute lung injury (ALI), ARDS and COVID-19 usually involve a “cytokine storm”. Insulin-like growth factor receptor 1 (IGF1R) maintains lung homeostasis and is implicated in these pulmonary inflammatory diseases. In mice, widespread IGF1R deficiency was reported to counteract respiratory inflammation and alveolar damage after bleomycin (BLM)-induced ALI. Methods. To explore the molecular mechanisms mediated by IGF1R signaling after BLM challenge, we performed RNA-sequencing in lungs of IGF1R-deficient mice after BLM or saline instillation, followed by differential expression and functional enrichment analyses. To further explore the findings, we performed protein immunodetection and DNA methylation measurements on lung sections and extracts, and analyses of primary MEFs lacking IGF1R. Results. Transcriptomic analysis identified differentially expressed genes between BLM-challenged and untreated control lungs, detecting biological processes and signaling pathways involved in ALI pathobiology. IGF1R depletion in BLM-challenged mice reversed large part of the transcriptional changes triggered by BLM, counteracting the transcriptomic profile of the inflammatory "cytokine storm". Data mining also identified changes in the expression of gene clusters with key roles in DNA damage, metabolic reprogramming, mitochondrial homeostasis, and epigenetics. These functional groups were deeply explored and further validated. IGF1R depleted MEFs exhibited decreased mitochondrial respiration and were protected against BLM-mediated morphological alterations, nuclear impairment and mitochondrial accumulation. Lung genomic DNA methylation levels in IGF1R-deficient BLM-challenged mice were found increased. Conclusions. These findings provide new insights into the molecular mechanisms underlying the attenuating effect of IGF1R deficiency on ALI, reinforce the important role of IGF1R in promoting ALI and postulate it as an epigenetic regulator in ARDS.