As
miRNAs are associated with normal cellular processes, deregulation of
miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of
miRNAs in fibrotic
lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current
therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify
miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of
miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung
fibrosis after
bleomycin exposure. This led to the identification of miR-199a-5p as the best
miRNA candidate associated with
bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of
pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral
ureteral obstruction mouse model of kidney
fibrosis, as well as in both bile duct
ligation and CCl4-induced mouse models of
liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue
fibrosis with therapeutic potency to treat fibroproliferative diseases.