Long Noncoding RNA Interleukin 6 Antisense RNA 1 Promotes Inflammatory Effects in Lung Macrophages via Exosomes Through the S100A9/TLR4 Pathway in Chronic Obstructive Pulmonary Disease Progression

This study investigates the role of interleukin 6 antisense RNA 1 (IL6-AS1), a highly expressed long noncoding RNA (lncRNA), in chronic obstructive pulmonary disease (COPD). An adeno-associated virus (AAV) was used to induce the expression of IL6-AS1 in mice, and they were exposed to cigarette smoke to establish a COPD model. IL6-AS1-overexpressing mice exposed to cigarette smoke demonstrated exacerbated COPD-like pathologies. Integrated with single-cell RNA sequencing analysis of COPD patients and pulmonary fibroblast-macrophage coculture system, our findings indicate that the upregulation of IL6-AS1 in fibroblasts enhances the interaction between the S100A9 protein and the AGER and TLR4 receptors on lung macrophages, thereby exacerbating pulmonary inflammation. The molecular mechanism likely involves exosome-mediated secretion, with IL6-AS1 binding to S100A9 protein. These findings suggest that IL6-AS1 may facilitate crosstalk between fibroblasts and macrophages, contributing to increased pulmonary inflammation, an effect that can be blocked by paquinimod. Mendelian randomization analysis further suggests a potential shared causal variant between IL6-AS1 and COPD risk. Taken together, this investigation provides valuable insights into the function of IL6-AS1 and its potential implications for the pathogenesis and therapeutic strategies in COPD.