Insights Into the Involvement of Circular RNAs in Autoimmune Diseases

Abstract

Circular RNAs (circRNAs) are single-stranded, endogenous, non-coding RNA (ncRNA) molecules formed by the backsplicing of messenger RNA (mRNA) precursors and have covalently closed circular structures without 5'-end caps and 3'-end polyadenylation [poly(A)] tails. CircRNAs are characterized by abundant species, stable structures, conserved sequences, cell- or tissue-specific expression, and widespread and stable presence in many organisms. Therefore, circRNAs can be used as biomarkers for the prediction, diagnosis, and treatment of a variety of diseases. Autoimmune diseases (AIDs) are caused by defects in immune tolerance or abnormal immune regulation, which leads to damage to host organs. Due to the complexity of the pathophysiological processes of AIDs, clinical therapeutics have been suboptimal. The emergence of circRNAs sheds new light on the treatment of AIDs. In particular, circRNAs mainly participate in the occurrence and development of AIDs by sponging targets. This review systematically explains the formation, function, mechanism, and characteristics of circRNAs in the context of AIDs. With a deeper understanding of the pathophysiological functions of circRNAs in the pathogenesis of AIDs, circRNAs may become reasonable, accurate, and effective biomarkers for the diagnosis and treatment of AIDs in the future.

Keywords: autoimmune diseases; autoimmune response; biomarker; circRNA; function.

Figure 1

Formation and types circRNAs (A) Intron-pairing driven cyclization, (B) RBP-driven cyclization, (C) Lariat-driven cyclization, (D) Single exon circRNA: circRNA composed of a single exon, (E) Multi-exon circRNA: circRNA composed of multiple exons, (F) CiRNA: circRNA composed of introns, (G) ElciRNA: circRNA composed of introns and exons.

Figure 2

Functions of circRNAs (a) CircRNAs are formed and processed in the nucleus. (b) MiRNA sponge: circRNAs contain many MREs to competitive combination of microRNAs, which can competitively inhibit the binding of mRNA to microRNAs to regulate the expression of genes. (c) CircRNA can adsorb proteins like sponge adsorption of microRNAs and regulate the activity of protein. (d) CircRNAs combined with proteins act as the bracket of RBP, provide a platform for interactions between proteins and DNA, RNA, or proteins, and rapidly respond to extracellular stimuli (e) CircRNAs can be translated into protein-like linear RNA. (f) CircRNAs containing m6A can bind and degrade through the YTHDF2–HRSP12-mediated RNA endonuclease RNase P/MRP complex. (g) CircRNAs can enter the exosomes to protect themselves from being cleared and play a role through exosome transfer to target cells.

Figure 3

Pathogenesis of autoimmune diseases (a) Autoantigen variation: the tolerance genes in the body are mutated by biological, chemical, and physical factors, resulting in new antigen determination clusters or previously hidden antigen epitopes present autoreactive T cells, leading to autoimmune response. (b) Cross immunoreaction: the antigen carried by the pathogen is the same as the auto-tissue antigen, which can stimulate the body to produce common antibodies and bind to the same epitope of different antigens, causing autoimmune diseases. (c) Abnormal regulation of immune responses: after the invasion of polyclonal stimulants (Polyclonal stimulant LPS, CpG ODNs) and pathogens, Th cells that recognize the antigenic determinant of the body's own components are still in a tolerant state, while Th cells that recognize the foreign antigenic determinant are activated to helper B cells, produce an immune response, and cause an autoimmune reaction. (d) Genetic factors: HLA genes can express MHC. When HLA genes are mutated, the abnormal expression produces mutated HLA antigen, which causes autoimmune responses.

Figure 4

The role of circRNAs in the pathophysiological process of SLE (a) In T cells of patients with SLE, hsa_circ_0012919 competitively binds to mir-125a-3P through ceRNA mechanism, regulates the expression of DNMT1/RANTES gene, reduces the level of CD70, and causes the pathophysiological process of acute and chronic inflammation, leading to the occurrence and development of SLE. CircIBTK competitively binds to mir-29b, reverses mir-29b induced DNA demethylation, activates the AKT signaling pathway, and promotes T cell apoptosis. CircRNA is degraded by RNase L, and PKR enhances phosphorylation when the organism is infected by an associated virus or stimulated by Poly (I:C), leading to the development of SLE. (b) In patients with SLE, the decrease in the number of T cells and B cells with excessive proliferation of antinuclear antibodies result in granulocyte cell membrane damage or degradation, swelling of the nucleus, the formation of lupus corpuscle, the induction of macrophages and neutrophils chemotaxis by LE corpuscle, combined with the formation of the antibody specificity immune complex, deposited on the skin, blood vessels, and joints. In the presence of the complement, lupus cells form, leading to inflammation and tissue necrosis, directly through autoantibodies and tissue cell antigen interaction, causing cell damage.

Figure 5

The role of circRNA in the pathophysiological process of RA (a) In synovial cells of patients with RA, hsa-circ-U0001045 competitively binds miR-30a, resulting in the overexpression of beclin-1 and LC3, promoting autophagy and the development and progression of RA. The downregulation of mir-671 resulted in the upregulation of CIRS-7, thereby reducing the inhibition of mir-7 on mTOR and affecting the pathophysiological process of RA through the PI3K/AKT/mTOR signaling pathway. (b) In patients with RA, EBV, bacteria, and other infectious factors enter the body, and its oligosaccharides, lipopeptide fragments, and other components are absorbed by synovium cells to form new proteoglycan, change the structure of IgG, and promote the body to produce a specific antibodies-rheumatoid factor. IgM, IgG, IgA, and IgE can combine with the RF to form immune complexes, which can be deposited in joints or local tissues, activate the complement, and produce C3a and C5a, prompting neutrophils and monocytes to englobe RF-IgG and other immune complexes, synthesize, and release lysosomal enzymes and IL-1 and other mediators, thereby causing the occurrence of RA.