Contribution of the STING in macrophages to the pulmonary inflammation and fibrosis.

Abstract

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays complex and context-dependent roles in the pathogenesis of fibrotic diseases. This study aimed to clarify the contributions of STING in the progression of pulmonary inflammation and fibrosis. We first evaluated STING1 gene expression across multiple lung diseases using publicly available datasets. To investigate its functional relevance, we established a Sting1-knockout (Sting1) mouse model and examined its effects on pulmonary inflammation and fibrosis induced by intranasal lipopolysaccharide (LPS) and bleomycin (BLM). The mRNA and protein expression in lung tissues were assessed using real-time quantitative PCR (RT-qPCR), immunohistochemistry (IHC), and western blotting (WB). Our results show that STING1 mRNA expression is significantly upregulated in interstitial pneumonia and positively correlates with inflammatory gene signatures. Notably, Sting1 deficiency attenuated LPS-induced acute lung inflammation and reduced macrophage infiltration. In contrast, Sting1 mice exhibited aggravated pulmonary fibrosis after BLM challenge. Mechanistically, Sting1 knockout enhanced endoplasmic reticulum (ER) stress and suppressed autophagic degradation in BLM-injured lungs. Moreover, Sting1 deficiency impaired mitochondrial respiration and phagocytic function in bone marrow-derived macrophages (BMDMs), suggesting that STING1 protects against inflammation-driven pulmonary fibrosis by promoting macrophage-mediated clearance of infectious stimuli. In summary, this study reveals a dual role for STING1 in pulmonary inflammation and fibrosis, underscoring its potential as a therapeutic target in the management of fibrotic diseases.