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.
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