Baricitinib alleviates myositis-associated interstitial lung disease in mice by inhibiting the NETs-cGAS-STING-EMT axis.

OBJECTIVE

Interstitial lung disease (ILD) is the most fatal complication in patients with polymyositis (PM) and dermatomyositis (DM). Baricitinib, a JAK1/JAK2 inhibitor, has demonstrated promising therapeutic effects in various inflammatory diseases. This study aimed to investigate the therapeutic role of baricitinib in PM/DM-ILD and its underlying mechanisms.

METHODS

A murine model of myositis-associated interstitial lung disease (MAILD) was established, and mice were randomly divided into high-dose Baricitinib, low-dose Baricitinib, model and control groups. Hematoxylin and eosin (HE) staining, Masson's trichrome staining, immunohistochemistry (IHC) and immunofluorescence (IF) staining were utilized to assess the degree of pulmonary fibrosis. For in vitro experiments, the A549 cell model was employed. RNA sequencing, Western blotting(WB), Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and IF were performed to detect neutrophil extracellular traps (NETs), epithelial-mesenchymal transition (EMT)-related markers and changes in the cGAS-STING signaling pathway.

RESULTS

In vivo experiments demonstrated that Baricitinib significantly alleviated pulmonary inflammation in MAILD mice and inhibited NETs-related markers, activation of the cGAS-STING pathway and EMT. In vitro experiments revealed that NETs upregulated the expression of mesenchymal markers (α-SMA and Vimentin), suppressed the epithelial marker E-cadherin and enhanced the activity of the cGAS-STING signaling pathway. Baricitinib was shown to counteract these effects.

CONCLUSION

Baricitinib significantly ameliorates pulmonary injury in MAILD mice by suppressing the formation of NETs, activation of the cGAS-STING signaling pathway and progression of EMT. This study provides an experimental foundation for the clinical application of baricitinib in PM/DM-ILD.