Baricitinib Alleviates Pulmonary Fibrosis in CIA Mice by Inhibiting M2 Macrophage Polarization and Increasing miR-126a-3p Expression in Macrophage-derived Exosomes

Background: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a severe condition with an unclear pathogenesis. We investigated the effects of baricitinib on lung fibrosis progression.Methods: A collagen-induced arthritis (CIA) mouse model was established. Lung tissues were analyzed using western blotting, immunofluorescence, and Masson's trichrome and hematoxylin and eosin staining. In vitro protein expression was assessed using western blotting and immunofluorescence. Supernatant cytokine levels were measured using ELISA, while macrophage-derived exosomes were identified using transmission electron microscopy, followed by microRNA sequencing analyses. miR-126a-3p-regulated genes were identified using dual luciferase reporter assays.Results: In vivo, baricitinib reduced CD206 levels and collagen deposition in CIA mice lungs through the JAK1-2/STAT pathway. In vitro, baricitinib downregulated the expression of arginase-1 and CD206 in macrophages and that of TGF-beta, IL-10, and IL-12 in supernatants. Baricitinib also increased miR-126a-3p expression in macrophage-derived exosomes. miR-126a-3p exerted antifibrotic effects by regulating apoptosis and autophagy via the PI3K/AKT1/mTOR pathway. Silencing JAK1 reduced JAK1 and JAK2 expression.Conclusion: Baricitinib, a dual JAK1/2 inhibitor, exerts superior antifibrotic effects and lowers the risk of pathway escape compared with JAK1- or JAK2-specific inhibitors by inhibiting M2 polarization, reducing fibrogenic cytokine levels, and increasing miR-126a-3p expression in macrophage-derived exosomes.