CCL2 is Upregulated by Decreased miR-122 Expression in Iron-Overload-Induced Hepatic Inflammation

Abstract

Background/Aims: Iron overload (IO) is accompanied by hepatic inflammation. The chemokine (C-C motif) ligand 2 (CCL2) mediates inflammation, and its overexpression is associated with IO. However, whether IO results in CCL2 overexpression in the liver and the underlying mechanisms are unclear. Methods: We subjected mice to IO by administering intraperitoneal injections of dextran-iron or by feeding mice a 3% dextran-iron diet to observe the effects of IO on miR-122/CCL2 expression through real-time qPCR and Western blot analysis. We also used indicators, including the expression of the inflammatory cytokine, the inflammation score based on H&E staining and the serum content of ALT and AST to evaluate the effects of IO on hepatic inflammation. Meanwhile, we observed the effects of vitamin E on IO-induced hepatic inflammation. In cells, we used 100 µΜ FeSO₄ or 30 µΜ Holo-Tf to produce IO and observed the roles of miR-122 in regulating CCL2 expression by using miR-122 mimics or inhibitors to overexpress or inhibit miR-122. Then, we used a dual-luciferase reporter assay to prove that miR-122 regulates CCL2 expression through direct binding to its complementary sequence in the CCL2 mRNA 3’UTR. Results: IO induces the downregulation of miR-122 and the upregulation of CCL2, as well as inflammatory responses both in vitro and in vivo. Although IO-induced oxidative stress is eliminated by the antioxidant vitamin E, IO-induced hepatic inflammation still exists, which probably can be explained by the fact that vitamin E has no effects on the miR-122/CCL2 pathway. In in vitro experiments, the overexpression and inhibition of miR-122 significantly reduced and increased CCL2 expression, respectively. The dual-luciferase reporter assay indicates that miR-122 binds CCL2 mRNA 3’UTR. Conclusion: We propose the roles of miR-122/CCL2 in IO-induced hepatic inflammation. Our studies should provide a new clue for developing clinical strategies for patients with IO.

Effect of iron chelation therapy on EPO-STAT5 signalling pathway and EPO resistance in iron-overloaded low-risk myelodysplastic syndrome patients

“…SOCS1 can be activated by EpoR stimulation and plays a negative regulatory effect on inflammation induced by cytokine [24]. With the MRI T2* technique, we found that the levels of iron deposition in the liver and heart of experience group patients were increased, which would affect the function of heart and liver and induce inflammatory reaction [25]. It is speculated that that a substantial increase in sEPO and inflammatory mediators could induce the increase of SOCS1 expression.…”

Inositol-Requiring Enzyme 1 Alpha Endoribonuclease Specific Inhibitor STF-083010 Alleviates Carbon Tetrachloride Induced Liver Injury and Liver Fibrosis in Mice

“…It was reported that pre-treatment with IRE1α inhibitor reduced pro-inflammatory cytokines production in tumor necrosis factor (TNF)-receptor-associated periodic fever syndrome (TRAPS) dermal fibroblasts (DFs) ( Harrison et al, 2018 ). On the other hand, these inflammatory cytokines were also the downstream target genes of miR-122 ( Hsu et al, 2012 ; Nakamura et al, 2015 ; Yin et al, 2016 ; Tang et al, 2017 ). In the present study, the result showed that STF-083010 evidently inhibited the upregulation of hepatic α-SMA, Col1α1 and Col1α2 in mice, but these also may be attributed to HSCs expression and the fact that STF-083010 alleviates liver injury by inhibiting CCl 4 -mediated hepatocyte death.…”

miR-155 and miR-122 Expression of Spermatozoa in Obese Subjects

“…MiR-122 inhibition increases the amount of mRNA transcribed by genes that control systemic iron levels, such as HFE, HJV, bone morphogenetic protein receptor type 1A (Bmpr1a), and HAMP ( Castoldi and Muckenthaler, 2012 ). Li et al (2017) and Tang et al (2017) have demonstrated that iron overload in mice induces the down-regulation of miR-122. Also, in patients with iron overload disorders, it was observed that miR-122 was decreased.…”