Abstract
BACKGROUND: Asthma is a heterogeneous group of diseases. The mechanism by which dysregulated circRNAs affect severe asthma by regulating macrophage polarization remains unclear. METHODS: High-throughput RNA sequencing technology was used to analyze circRNA expression in peripheral blood mononuclear cells (PBMCs) from patients with severe asthma. RT-qPCR and ELISA were used to analyze the expression of inflammatory factors in a mouse model of severe asthma induced by ovalbumin-lipopolysaccharide. The effect of circ-0001875 on macrophage activation and the underlying mechanism were analyzed by RT-qPCR, Western blot, and ELISA. Subsequently, the regulatory relationships among circ-0001875, miR-31-5p, and SP1 were examined through dual luciferase reporter gene assay, and the mechanism by which they regulate macrophage polarization was analyzed by Western blot. RESULTS: Compared with the healthy control group, 420 circRNAs were differentially expressed in PBMCs from patients with severe asthma. Among them, circ-0001875, which was mainly expressed in the cytoplasm of monocytes, was significantly downregulated in asthmatics, especially those with severe disease. circ-0001875 overexpression inhibited M1 macrophage activation in vitro and alleviated lung inflammation in a mouse model of severe asthma. Mechanistically, circ-0001875 promoted SP1 translation by competitively binding to miR-31-5p, thereby reducing its inhibitory effect on SP1 translation; SP1 then inhibited M1 macrophage polarization, which is associated with severe asthma, through the NF-κB signaling pathway. CONCLUSIONS: We found that circ-0001875 plays an important role in regulating M1 macrophage polarization, which is associated with a severe pro-inflammatory response.