MiR-223 as a Regulator and Therapeutic Target in Liver Diseases

Abstract

MicroRNAs (miRNAs) are endogenous non-coding single-stranded small molecule RNAs consisting of 20-24 nucleotides that are highly conserved in species evolution. Expression of miRNAs is strictly tissue-specific, and it is chronological in fungi and plants, as well as in animals. MiR-223 has been shown to play a key role in innate immunity, and dysregulation of its expression contributes to the pathogenesis of multiple inflammatory diseases, and cancers. In this article the biosynthesis and functions of miR-223 in innate immunity are reviewed, and the role of miR-223 in liver physiopathology and therapeutic prospects are highlighted.

Keywords: inflammation; liver disease; macrophage; miR-223; neutrophil.

Figure 1

Biological function prediction of miR-223 target genes. Functions of miR-223 target genes analyzed in TargetScan database (A), miRDB database (B), and miRanda database (C). (D) The intersecting target genes of the three databases.

Figure 2

MiR-223 target genes. Combined with miRTarBase database, the target gene network of miR-223 was constructed. The green shapes represent experimentally validated target genes that have been reported, and the red shapes represent target genes that have not been experimentally validated yet.

Figure 3

Role of miR-223 in acute liver injury. (A) In ConA-induced liver injury, miR-223 inhibits IL-1β production by suppressing inflammasome AIM2 in Kupffer cells. (B) During APAP-induced liver injury, mtDNA released from damaged hepatocytes activates NF-κB depending on TLR9-pathway and subsequently increases expression of inflammatory genes, thereby enhancing liver injury. Meanwhile, mtDNA/TLR9/NF-κB signaling also up-regulates expression of miR-223 in neutrophils. MiR-223 then acts as a negative feedback loop to ameliorate APAP-induced liver injury by targeting IKKα. During Fas-induced hepatocyte apoptosis, miR-223 enhances Fas-induced hepatocyte apoptosis and liver injury by targeting the insulin-like growth factor 1 receptor (IGF1R).

Figure 4

Role of miR-223 in the progression of NAFLD and ALD. During HFD, free fatty acids elevate miR-223 expression in neutrophils by regulating APOE/PU.1 signaling. MiR-223 directly targets NLRP3, CXCL2, IL-6 to ameliorate inflammatory responses. And miR-223 can also form a feedback loop to prevent NASH progression by promoting the preferential uptake of neutrophil-derived miR-223/APOE-enriched EVs in hepatocytes. IL-6 signaling promotes macrophages to release miR-223-enriched exosomes that inhibit expression of several miR-223-targeted genes in hepatocytes, thereby attenuating NASH-associated liver fibrosis. In addition, PPARγ/miR-223 axis control macrophage polarization and protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance. PPARγ can enhance miR-223 expression by directly binding to pre-miR-223 promoter. MiR-223 is required for PPARγ-induced M2 macrophage polarization by controlling expression of the target genes Nfat5 and Rasa1. Moreover, miR-223 inhibits Pknox1 expression, thereby suppressing proinflammatory activation of M1 response. Ethanol elevates miR-223 levels. MiR-223 attenuates neutrophil function by inhibiting the IL-6–p47phox–ROS pathway, thereby protecting against ALD.

Figure 5

Role of miR-223 in HCC. In HCC, sulfatide acts on the promoter region of pre-miR-223, thereby reducing the recruitment of histone H3 with C/EBPα and decreasing miR-223 expression. MiR-223 directly targets Rab1, NLRP3, Stathmin1, FBW7, and FOXO3a, which involved in tumor cell proliferation, apoptosis, autophagy, and drug resistance.