MicroRNAs: Essential players in the regulation of inflammation Ana Rebane, PhD, Cezmi A. Akdis, MD  Journal of Allergy and Clinical Immunology  Volume 132, Issue 1, Pages 15-26 (July 2013) DOI: 10.1016/j.jaci.2013.04.011 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Biogenesis and mechanism of action of miRNAs. miRNAs are synthesized in the nucleus by RNA polymerase II as part of longer transcripts. These long pri-miRNAs are cleaved by the Drosha-DGCR8 complex to hairpin-like pre-miRNAs. Pre-miRNAs are exported to the cytoplasm by the exportin-5-RAN-GTP complex, where they are further processed by Dicer to a short RNA duplex. One strand of the duplex is incorporated into the RISC complex containing the AGO2 and GW182 proteins. The second strand can be loaded into another RISC complex or is degraded. The GW182 protein mediates recruitment of the CCR4-NOT nuclease complex, followed by inhibition of translation, deadenylation, and degradation of mRNA. Journal of Allergy and Clinical Immunology 2013 132, 15-26DOI: (10.1016/j.jaci.2013.04.011) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Functions of selected miRNAs in antigen-presenting cells (APCs), T cells, and epithelial cells. miR-146a targets TLR2/4 and TCR-signaling pathways through downregulation of IRAK1 and TNF receptor–associated factor 6 (TRAF6). In Treg cells miR-146a suppresses STAT1 and IFN-γ production. miR-181a downregulates dual-specific phosphatase 6 (DUSP6) expression and therefore activates extracellular signal-regulated kinase (ERK), which enhances TCR sensitivity. Increased expression of the miR-17–92 cluster leads to suppression of phosphatase and tensin homolog, which causes reduced T-cell deaths. In APCs miR-155 targets SOCS1 and thereby activates the Janus kinase–STAT pathway, followed by type I interferon production. miR-155 also suppresses IL-13RA1. miR-21 targets programmed cell death 4 and IL-12p35 and suppresses the activation of NF-κB. miR-511 is expressed in APCs and promotes the expression of its target TLR4 in unknown mechanism. Sustained expression of miR-132/212 results in downregulation of IRAK4 and tolerance to TLR2-dependent stimulation. miR-223 targets NLRP3 and inhibits IL-1β production from the inflammasome. miR-125b and miR-187 target TNF-α. In keratinocytes miR-125b suppresses fibroblast growth factor receptor 2 (FGFR2) and proliferation. In gut mucosal epithelial cells miR-375 induces the expression of TSLP through targeting Kruppel-like factor 5 (KLF5). PDCD4, Programmed cell death 4; PTEN, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase, phosphatase and tensin homolog; TRAF6, TNF receptor–associated factor 6. Journal of Allergy and Clinical Immunology 2013 132, 15-26DOI: (10.1016/j.jaci.2013.04.011) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions