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

Abstract

Rationale: 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. Methods: 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 circPPM1F in vitro . The regulatory role of circPPM1F in vivo was evaluated in the streptozocin-induced diabetic mouse model. Results: We identified 27 upregulated and 31 downregulated differentially expressed circRNAs in T1DM patients. circPPM1F , a circRNA with unknown function, was dominantly expressed in monocytes and significantly upregulated in T1DM patients. Functionally, circPPM1F promoted lipopolysaccharide (LPS)-induced M1 macrophage activation via enhancement of the NF-κB signaling pathway. Mechanistically, circPPM1F competitively interacted with HuR to impair the translation of protein phosphatase, Mg 2+ /Mn 2+ 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 circPPM1F expression during M1 macrophage activation. In addition, circPPM1F could exacerbate pancreas injury in the streptozocin-induced diabetic mice by activation of M1 macrophages in vivo . Conclusions: circPPM1F is a novel positive regulator of M1 macrophage activation through the circPPM1F -HuR-PPM1F-NF-κB axis. Overexpression of circPPM1F could promote pancreatic islet injury by enhancing M1 macrophage activation and circPPM1F may serve as a novel potential therapeutic target for T1DM in children.

Non-coding RNAs regulation of macrophage polarization in cancer

“…For example, discoveries could convert a simple tumor suppressor into a juggling tumor suppressor depending on the new findings about the functional role of ncRNAs. However, no reported studies were found yet in the literature that demonstrated the role of other ncRNAs (excluding miRNAs and lncRNAs) in regulating macrophagic polarization in different cancers, although few ones are related to non-cancer diseases [ 131 ].…”

Involvement of circRNAs in Proinflammatory Cytokines-Mediated β-Cell Dysfunction

“…Inhibition of circHIPK3 and ciRS-7/CDR1as in the islets of wild type animals resulted in impaired insulin secretion, reduced β -cell proliferation, and survival [ 12 ]. Circular RNA circPPM1F modulates M1 macrophage activation and pancreatic islet inflammation in type 1 diabetes [ 34 ]. Circulating circular RNA profiles have also been reported to be associated with type 1 diabetes [ 35 ].…”

Understanding Competitive Endogenous RNA Network Mechanism in Type 1 Diabetes Mellitus Using Computational and Bioinformatics Approaches

“…One is the circRNA, lncRNA, and mRNA expression profile GSE133225, and the other one is the miRNA expression profile GSE133217. Both expression profiles were provided by Zhang Caiyan and Zhou Yufeng, 25 , 36 and included 4 peripheral blood mononuclear cells (PBMCs) samples from T1DM patients and 4 PBMCs samples from healthy volunteers.…”

“… 24 Another study by Zhang et al found that circRNA circPPM1F modulates M1 macrophage activation and pancreatic islet inflammation in T1DM. 25 Therefore, examining the expression of lncRNAs and circRNAs and exploring their underlying mechanism in T1DM opens avenues to a better understanding of the T1DM pathogenesis.…”