Circular RNA Modulates M1 Macrophage Activation and Pancreatic Islet Inflammation in Type 1 Diabetes Mellitus

Macrophages play critical roles in the pathogenesis of type 1 diabetes mellitus (T1DM). Circular RNAs (circRNAs) are a novel class of endogenous RNAs with covalently closed loop structures, implicated in various disease processes. However, their impact on macrophage activation and T1DM pathogenesis remains elusive. circRNA expression profiles of peripheral blood mononuclear cells (PBMCs) from T1DM children were determined by whole transcriptome microarray. Bioinformatics, quantitative real-time PCR, Western blot, RNA immunoprecipitation (RIP), cell co-culture, cell proliferation, and cell apoptosis assays were performed to investigate the expression, function, and regulatory mechanisms of . The regulatory role of was evaluated in the streptozocin-induced diabetic mouse model. We identified 27 upregulated and 31 downregulated differentially expressed circRNAs in T1DM patients. , a circRNA with unknown function, was dominantly expressed in monocytes and significantly upregulated in T1DM patients. Functionally, promoted lipopolysaccharide (LPS)-induced M1 macrophage activation via enhancement of the NF-κB signaling pathway. Mechanistically, competitively interacted with HuR to impair the translation of protein phosphatase, Mg/Mn dependent 1F (PPM1F), thus alleviating the inhibitory effect of PPM1F on the NF-κB pathway. Moreover, eukaryotic initiation factor 4A-III (EIF4A3) and fused in sarcoma (FUS) coordinately regulated expression during M1 macrophage activation. In addition, could exacerbate pancreas injury in the streptozocin-induced diabetic mice by activation of M1 macrophages . is a novel positive regulator of M1 macrophage activation through the -HuR-PPM1F-NF-κB axis. Overexpression of could promote pancreatic islet injury by enhancing M1 macrophage activation and may serve as a novel potential therapeutic target for T1DM in children.