MicroRNAs in the regulation of TLR and RIG-I pathways

Abstract

The innate immune system recognizes invading pathogens through germline-encoded pattern recognition receptors (PRRs), which elicit innate antimicrobial and inflammatory responses and initiate adaptive immunity to control or eliminate infection. Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) are the key innate immune PRRs and are tightly regulated by elaborate mechanisms to ensure a beneficial outcome in response to foreign invaders. Although much of the focus in the literature has been on the study of protein regulators of inflammation, microRNAs (miRNAs) have emerged as important controllers of certain features of the inflammatory process. Several miRNAs are induced by TLR and RIG-I activation in myeloid cells and act as feedback regulators of TLR and RIG-I signaling. In this review, we comprehensively discuss the recent understanding of how miRNA networks respond to TLR and RIG-I signaling and their role in the initiation and termination of inflammatory responses. Increasing evidence also indicates that both virus-encoded miRNAs and cellular miRNAs have important functions in viral replication and host anti-viral immunity.

miR-146a is directly regulated by STAT3 in human hepatocellular carcinoma cells and involved in anti-tumor immune suppression

“…However, the accumulated studies have revealed that miR-146a can induce the resistance to type I IFN by targeting STAT1, 25,27 and downregulate type I IFN expression by targeting IRAK1 and TRAF6. 43 Here, we also observed that STAT3 blockage upregulated STAT1 and TRAF6, as well as the downstream genes of type I IFN pathway. And type I IFN, which is critical for NK cell activation by blocking STAT3 in HCC cells, 4 could be increased by miR-146a inhibition accompanied with reversing HCC-mediated inhibitory effects on NK cells.…”

MicroRNA-15b Modulates Japanese Encephalitis Virus–Mediated Inflammation via Targeting RNF125

“…Many proteins are known to modify the RIG-I pathway and the subsequent cytokine signal transduction (34,51,57,58), but the role of miRNA-mediated regulation is only beginning to emerge. Thus, the level of receptor expression is the first and likely effective point at which miRNAs exert their functions, but few studies have focused on the regulation of RIG-I expression by miRNAs (18). In this study, JEV infection induced miR-15b expression, and miR-15b increased JEV-induced expression of RIG-I, coincident with enhanced IRF3 signaling and NF-kB signaling, by targeting a regulon of RIG-I, RNF125.…”

“…Following JEV invasion, glial cells play an essential role in the immune response against pathogens; however, viral replication within glial cells leads to bystander neuronal death by secretion of inflammatory mediators (6). miRNAs have emerged as a major class of gene-expression regulators implicated in the immune response during inflammation and/or infections (17,18). Thus, in this study, we aimed to address the role of miRNA-regulated pathways in the JEV-induced neuroinflammation model.…”

“…The role of miRNAs has been widely studied in the regulation of a broad spectrum of cellular processes, including proliferation and differentiation, cancer, apoptosis, and viral infections (14)(15)(16)(17). Recently, these small RNAs also were found to be involved in the TLR and RIG-I signaling pathways of the innate immune system (18). In addition, miR-146a, miR-21, and miR-155 are regarded as regulators of IFN signaling and inflammatory responses at multiple levels (19)(20)(21).…”

In vitro screening of LPS-induced miRNAs in leukocytes derived from cord blood and their possible roles in regulating TLR signals

“…miRNAs have been identified as important regulators of immune responses (7) and as fine-tuners of TLRs (8). Multiple molecules involved in the TLR pathway are thought to be targeted by miRNAs, such as the expression of the TLRs themselves, TLR signal molecules, TLR-induced transcription factors, regulators of the TLR signaling pathway, and even the final functional cytokines involved in TLR signaling (9).…”