MicroRNA-223 restricts liver fibrosis by inhibiting the TAZ-IHH-GLI2 and PDGF signaling pathways via the crosstalk of multiple liver cell types

Abstract

Background & Aims: Liver fibrosis is a common consequence of chronic liver injury and is characterized by the accumulation of extracellular matrix mainly generated from activated hepatic stellate cells (HSCs). At present, the mechanisms underlying liver fibrogenesis remain obscure and effective pharmacological therapies are lacking. Neutrophil-specific microRNA-223 (miR-223) plays an important role in controlling the development of various liver diseases; however, its role in HSC activation and liver fibrosis remains unclear. Methods: Liver fibrosis was induced by chronic carbon tetrachloride (CCl4) injection of miR-223 knockout (miR-223KO) mice and littermate wild-type controls. MiR-223 was overexpressed in cultured HSCs to determine its function and targets during HSC activation and proliferation. The expression of miR-223 and pri-miR-223 was examined in primary HSCs isolated from CCl4-treated mice and in cultured HSCs. The communication between HSCs and neutrophils was studied by performing in vitro co-culture experiments. Results: Genetic deletion of miR-223 exacerbated chronic CCl4-induced liver fibrosis. Administration of miR-223 inhibited liver fibrosis by inhibiting the transcriptional coactivator with PDZ-binding motif (TAZ)-Indian hedgehog (IHH)-GLI Family Zinc Finger 2 (GLI2) pathway via the crosstalk between hepatocytes and HSCs. Overexpression of miR-223 also directly attenuated Gli2 as well as platelet-derived growth factor receptor α/β (Pdgfra/b) expression in HSCs, thereby suppressing HSC activation and proliferation. The expression of pri-miR-223 and miR-223 was downregulated during HSC activation in vitro. Expression of pri-miR-223 was also decreased in activated HSCs in vivo in fibrotic livers but mature miR-223 expression was not reduced. Finally, in co-culture experiments, activated HSCs were able to take up miR-223-enriched extracellular vesicles from neutrophils, resulting in elevation of miR-223. Conclusion: MiR-223 restricts liver fibrosis by targeting multiple genes in hepatocytes and HSCs, providing potential therapeutic targets for the treatment of liver fibrosis.

Role of Neutrophils in the Pathogenesis of Nonalcoholic Steatohepatitis

“…In particular, the transfer of miR-223-enriched EVs is mediated by the interaction between low-density lipoprotein receptor (LDLR) in hepatocytes and apolipoprotein E (APOE) in EVs ( 118 ). In addition, miR-223 protects against liver fibrosis by targeting multiple genes in hepatocytes and HSCs ( 120 ), which may contribute to the role of miR-223 in preventing NASH progression. The IL-6 signaling in myeloid cells, such as neutrophils, is important for the generation and release of miR-223-enriched EVs, which may inhibit the progression of fibrosis in NASH-associated fibrosis ( 121 , 122 ).…”

Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure

“…We previously reported that genetic deletion of the miR-223 gene exacerbated ethanol-induced hepatic injury, neutrophil infiltration, ROS, and upregulated hepatic expression of p47 phox ( 21 ), suggesting that miR-223 plays an important role in inhibiting liver inflammation. miR-223 has also been shown to block hepatic fibrosis ( 30 , 48 , 49 ). Interestingly, our RNA-Seq data indicate significant downregulation of several miR-223–targeted genes associated with inflammation and fibrosis ( 28 – 30 ) in ethanol-fed Ncf1 Lyz–/– mice.…”

Insights Into the Role of Platelet-Derived Growth Factors: Implications for Parkinson’s Disease Pathogenesis and Treatment

“…(Si et al, 2021) miR-223 Overexpression of miR-223 alleviates GLI family zinc finger 2and platelet-derived growth factor receptor α/βexpression in hepatic stellate cells (HSCs), thus inhibiting the activation and proliferation of HSC. (Wang et al, 2021) miR-29a At the transcriptional and translational levels miR-29a decrease the expressions of PDGFC and PDGFA. (Yang et al, 2019b) miR-26b-5p MiR-26b-5p produces a negative adjustment of PDGFR-β and interacts with non-coding RNA maternally expressed gene (lncMEG3).…”