MicroRNA-674-5p/5-LO axis involved in autoimmune reaction of Concanavalin A-induced acute mouse liver injury

Abstract

Autoimmune hepatitis is characterized, in part, by the pathways involving cysteinyl-leukotriene metabolites of arachidonic acid, the dynamics of which remain unclear. Here, we explored post-transcriptional regulation in the 5-lipoxygenase (5-LO) pathway of arachidonic acid in a Concanavalin A (Con A) induced mouse model. We found that Con A administration lead to 5-LO overexpression and cysteinyl-leukotriene release in early hepatic injury, which was attenuated by cyclosporin A pretreatment. Subsequent microarray and qRT-PCR analysis further showed that microRNA-674-5p (miR-674-5p) displayed a significant decrease in expression in Con A-damaged liver. Noting that miR-674-5p harbors a potential binding region for 5-LO, we further transfected hepatic cell lines with overexpressing miR-674-5p mimic and discovered a negative regulating effect of miR-674-5p on 5-LO expression in the presence of IL-6 or TNF-α. These findings suggest that miR-674-5p might be a negative regulator in 5-LO mediated autoimmune liver injury, representing a compelling avenue towards future therapeutic interventions.

β-arrestin-biased agonism of β-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling

“…Our recent study indeed demonstrated that one of them, miR-532-5p protects the heart against AMI [47]. Although miR-466g has been shown to play a role in renal epithelial cells [67], and miR-674 has been implicated in immune responses and liver injury [68, 69], neither of these two newly identified β-arrestin-responsive miRs have been reported to play a functional role in either cardiac cells or heart tissues. Interestingly, we report novel findings that (i) knockdown of miR-466g increases CEC apoptosis, but decreases migration and proliferation of CECs, and (ii) knockdown of miR-674 decreases migration and proliferation of CFs.…”

Characterization and functional prediction of the microRNAs differentially expressed in a mouse model of concanavalin A-induced autoimmune hepatitis

“…So far, a number of miRNAs have been proved to be the important negative regulators taking part in the development of AIH [21][22][23][24][25]. However, the exact changes of miRNA expression profiling in AIH have not been reported.…”

Regulation of Eicosanoid Pathways by MicroRNAs

“…It is known that the combination of alternative splicing and RNA decay modulates 5-LO gene expression (Ochs et al, 2012). Furthermore, several publications demonstrated that 5-LO is a canonical target for miR-19a-3p, miR-125-5p (Busch et al, 2015), miR-216-3p (Wang et al, 2018), and miR-674-5p (Su et al, 2016) (see Table 2 ). Specifically, miR-19a-3p and miR-125-5p regulate 5-LO expression in the human myeloid cell line MonoMac 6.…”

“…MiR-674-5p was identified as a direct regulator of 5-LO mRNA in mice. It is further discussed as a negative regulator in 5-LO-mediated autoimmune diseases of the liver, thus representing a promising approach to future therapeutic measures (Su et al, 2016). Recently, it was shown that miR-216a-3p regulates not only COX-2 but also 5-LO expression in colon cancer, thus affecting colon cancer cell proliferation.…”