MiR-185/AKT and miR-29a/collagen 1a pathways are activated in IPF alveolar macrophages

MicroRNA expression signatures of the BALF cells and in particular the alveolar macrophages are currently lacking despite the extensive characterisaion of microRNA expression in IPF tissues, isolated fibroblasts and mouse lungs. Here we sought to investigate the existence of IPF associated microRNA expression in the cellular component of the BAL fluid and we thus focused in the expression of microRNAs previously associated with fibrosis (miR-29a, b, c, let-7d, and miR-21) and rapid IPF progression (miR-185, miR-210, miR- 302c-3p miR-376c and 423-5p). IPF BAL fluid cells displayed a pro-fibrotic profile with miR-29a downregulation and increased expression of its target, COL1A1 mRNA. Furthermore, miR-29a downregulation was significantly associated with lower DLCO% and eosinophil infiltration of the alveolar spaces. Tumour-suppressor miR-185 was also significantly downregulated in IPF BAL fluid cells. MiR-185 downregulation was associated with significantly increased AKT total protein levels and AKT ser473 phosphorylation in the IPF group relative to the controls. The role of miR-185 in AKT activation was confirmed in THP-1 cells transfected with a miR-185 inhibitor that resulted in a significant increase in AKT1 mRNA and AKT ser473 phosphorylation. Our study identifies significant differences in miR-29a/collagen and miR-185/AKT axes in the BALF cells of IPF patients and highlight the relevance and importance of BALF microRNA signatures in IPF.