Figure 3.

Immune response involving circRNAs in SARS-CoV-2 infection and the potential mechanism of circRNAs in inflammation. During virus infection, nuclear factor 90 (NF90) and its 110 (NF110) isoform produced by interleukin-enhanced binding factor 3 (ILF3) bind to viral mRNA to inhibit virus replication through two pathways: transport from the nucleus to the cytoplasm and decoupling from the circRNA-protein complex (CircRNPs) in the cytoplasm. Among them, the transport of NF90/NF110 from the nucleus to the cytoplasm can reduce the expression of circRNAs. In contrast, the binding of NF90/NF110 to dsRNA formed during pre-mRNA processing can not only stabilize the RNA duplex but also promote reverse splicing to form circRNA (57). 2’-5’ Oligoadenylate (2’-5’A) is generated by the combination of 2’-5’ oligoadenylate synthase (OAS) and viral genome dsRNA and plays an antiviral effect by significantly increasing the activity of RNase L to degrade viral RNA and interfere with viral protein synthesis. Endogenous circRNAs often form incomplete RNA duplexes and act as inhibitors of PKR activation by dsRNAs associated with innate immunity. Meanwhile, circRNAs can be globally degraded by the endonuclease RNase L to activate the PKR antiviral pathway (77). In addition, parental genes enriched for differentially expressed circRNAs in signalling pathways that are significantly regulated upon SARS-CoV-2 infection are associated with multiple antiviral signalling pathways (16, 74, 78). The generation of a cytokine storm is related to the overproduction of proinflammatory cytokines mediated by circRNAs. In macrophages, circ_09505 acts as a sponge of miR-6089 through the IκBα/NFκB signalling pathway, on the one hand, promoting the expression of AKT1 in macrophages and the activation of NF-κB, and on the other hand, promoting the production of the proinflammatory cytokines TNF-α, IL-6 and IL-12 (79). Furthermore, circ_0044073 in HUVSMCs and HUVECs functions as a miR-107 sponge to downregulate the expression levels of target mRNAs, while activation of the JAK/STAT signalling pathway enhanced the expression of the downstream proteins Bcl2 and c-myc. Moreover, circ_0044073 significantly upregulated the levels of the proinflammatory cytokines IL-1β, IL-6 and TNF-α (80). In addition, the occurrence of a cytokine storm disrupts the balance of proinflammatory and anti-inflammatory mechanisms, thereby invading the patient’s nervous system (81, 82).