MicroRNA-146a Feedback Inhibits RIG-I-Dependent Type I IFN Production in Macrophages by Targeting TRAF6, IRAK1, and IRAK2

Abstract

Upon recognition of viral components by pattern recognition receptors, including TLRs and retinoic acid-inducible gene I (RIG-I)- like helicases, cells are activated to produce type I IFN and proinflammatory cytokines. These pathways are tightly regulated by host to prevent inappropriate cellular response, but viruses can down-regulate these pathways for their survival. Recently, identification of negative regulators for cytoplasmic RNA-mediated antiviral signaling, especially the RIG-I pathway, attract much attention. However, there is no report about negative regulation of RIG-I antiviral pathway by microRNAs (miRNA) to date. We found that vesicular stomatitis virus (VSV) infection up-regulated miR-146a expression in mouse macrophages in TLR-myeloid differentiation factor 88-independent but RIG-I-NF-κB-dependent manner. In turn, miR-146a negatively regulated VSV-triggered type I IFN production, thus promoting VSV replication in macrophages. In addition to two known miR-146a targets, TRAF6 and IRAK1, we proved that IRAK2 was another target of miR-146a, which also participated in VSV-induced type I IFN production. Furthermore, IRAK1 and IRAK2 participated in VSV-induced type I IFN production by associating with Fas-associated death domain protein, an important adaptor in RIG-I signaling, in a VSV infection-inducible manner. Therefore, we demonstrate that miR-146a, up-regulated during viral infection, is a negative regulator of the RIG-I-dependent antiviral pathway by targeting TRAF6, IRAK1, and IRAK2.

Chronic Lymphocytic Leukemia: A Paradigm of Innate Immune Cross-Tolerance

“…Several investigators suggested that ET in human monocytes and mouse macrophages is associated with decreased TLR4-MyD88-IRAK complex formation, impairment of IRAK-1 activity, and TRAF6 expression (45)(46)(47)(48)(49). In this regard, miRNAs have emerged as an important regulatory mechanism for gene expression of a number of TLR4 pathway components during ET (49); in particular, miR146a is critical for ET development in human monocytes (48,(50)(51)(52)(53)(54). As shown in Fig.…”

MicroRNAs in the regulation of TLR and RIG-I pathways

“…The regulatory mechanisms of the RIG-I signaling pathway are similar to the ones described above, although the regulation has not yet been clearly defined. 70 These data indicate that the immune system utilizes multiple miRNAs to properly regulate its functional capacity, creating a finely tuned balance between activation and repression. Nonetheless, the precise regulatory roles of miRNAs in TLR and RIG-I responses are still not fully understood, especially how these miRNA networks collaborate together to optimize immune responses.…”

“…Recently, IRAK2, a kinase that compensates for IRAK1 to activate NF-kB, has also been confirmed as a miR-146 target. 70 Other key TLR signaling pathway components have also been demonstrated as miRNA targets. MyD88 adaptor-like protein, which functions as a bridge for the TLR2 and TLR4-mediated MyD88-dependent pathway, has emerged as a miR-145 target, 80 although the miR-145 expression profile following TLR agonist stimulation remains undetermined.…”

“…VSV Infection in macrophages induces miR-146a expression in a TLR/MyD88-independent/ RIG-I-dependent manner, and miR-146a sequentially suppresses VSV-triggered type I IFN production by targeting IRAK1, IRAK2 and TNFR-associated factor 6, thus promoting VSV replication. 70 Recently, we have demonstrated that miR-466l can directly bind to the 39-UTR of IFN-a and reduce its expression during VSV infection. 111 There is mounting evidence that type I IFN can manipulate miRNA expression.…”

“…For example, vesicular stomatitis virus (VSV) infection upregulates miR-146a expression in mouse macrophages in a TLR/MyD88-independent and RIG-I/NFkB-dependent manner. 70 VSV infection has been recently shown to induce miR-155 expression in macrophages, which promotes type I IFN signaling and has an antiviral effect by targeting SOCS1. 71 MiRNA-mediated regulation of TLR signaling pathway Targeting TLR expression.…”