Roles of circular RNAs in immune regulation and autoimmune diseases

Abstract

Circular RNAs (circRNAs), as a novel class of endogenously expressed non-coding RNAs (ncRNAs), have a high stability and often present tissue-specific expression and evolutionary conservation. Emerging evidence has suggested that circRNAs play an essential role in complex human pathologies. Notably, circRNAs, important gene modulators in the immune system, are strongly associated with the occurrence and development of autoimmune diseases. Here, we focus on the roles of circRNAs in immune cells and immune regulation, highlighting their potential as biomarkers and biological functions in autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), primary biliary cholangitis (PBC), and psoriasis, aiming at providing new insights into the diagnosis and therapy of these diseases.

Fig. 1. Formation of circRNAs by pre-mRNA back-splicing events.

a The intron complementary repeat sequences or RNA-binding proteins such as QKI, MBL, and NF90/NF110 promote the back-splicing. b A lariat containing one or more skipped exons is re-spliced to generate a circRNA and a double lariat, and the circRNA may be an EIciRNAs or an ecircRNA. c CiRNA is generated from the intron lariat

Fig. 2. CircRNAs in immune regulation.

NF90/NF110 enhance back-splicing by stabilizing the intron complementary sequence pairs in the nucleus and are exported to the cytoplasm to suppress viral replication after viral infection. The exogenous circRNA induces innate immune response by activating RIG-I, whereas the endogenous circRNA binds to different RNA-binding proteins that reflect its endogenous biogenesis. hsa_circ_0005105 facilitates the expression of inflammatory cytokines by regulating the miR-26a targeted NAMPT. has_circ_0020397 promotes the expression of PD-L1 by binding to miR-138, thereby participating in tumor immunity. In addition, mcircRasGEF1B induced by LPS is involved in anti-bacteria immunity by modulating the stability of ICAM-1 mRNAs

Fig. 3. Roles of circRNAs in autoimmune diseases.

CircRNAs contribute to the development of autoimmune diseases by regulating various biological processes, such as DNA methylation, immune response, and inflammatory response. Furthermore, circRNAs may be used as potential biomarkers for the diagnosis and severity of autoimmune diseases. The overexpression of cia-cGAS can suppress IFN expression in TREX1-deficient BMDMs. The overexpression of dsRNA-containing circRNAs alleviate the aberrant PKR activation cascade in SLE patient-derived cells