Circular RNA<i> circPPM1F</i> modulates M1 macrophage activation and pancreatic islet inflammation in type 1 diabetes mellitus

<b>Rationale:</b> 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. <b>Methods:</b> 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 <i>circPPM1F in vitro</i>. The regulatory role of <i>circPPM1F in vivo</i> was evaluated in the streptozocin-induced diabetic mouse model. <b>Results:</b> We identified 27 upregulated and 31 downregulated differentially expressed circRNAs in T1DM patients. <i>circPPM1F</i>, a circRNA with unknown function, was dominantly expressed in monocytes and significantly upregulated in T1DM patients. Functionally, <i>circPPM1F</i> promoted lipopolysaccharide (LPS)-induced M1 macrophage activation via enhancement of the NF-κB signaling pathway. Mechanistically, <i>circPPM1F</i> competitively interacted with HuR to impair the translation of protein phosphatase, Mg²⁺/Mn²⁺ 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 <i>circPPM1F</i> expression during M1 macrophage activation. In addition, <i>circPPM1F</i> could exacerbate pancreas injury in the streptozocin-induced diabetic mice by activation of M1 macrophages <i>in vivo</i>. <b>Conclusions:</b><i>circPPM1F</i> is a novel positive regulator of M1 macrophage activation through the <i>circPPM1F</i>-HuR-PPM1F-NF-κB axis. Overexpression of <i>circPPM1F</i> could promote pancreatic islet injury by enhancing M1 macrophage activation and <i>circPPM1F</i> may serve as a novel potential therapeutic target for T1DM in children.