miR-146a Ameliorates Liver Ischemia/Reperfusion Injury by Suppressing IRAK1 and TRAF6

Abstract

A critical role of the Toll-like receptor(TLR) and its downstream molecules, including IL-1 receptor-associated kinase 1(IRAK1) and tumor necrosis factor receptor– associated factor 6(TRAF6), in the pathogenesis of liver ischemia/reperfusion (I/R) injury has been documented. Recently a microRNA, miR-146a, was identified as a potent negative regulator of the TLR signaling pathway. In this study, we investigated the role of miR-146a to attenuate TLR signaling and liver I/R injury in vivo and in vitro. miR-146a was decreased in mice Kupffer cells following hepatic I/R, whereas IRAK1 and TRAF6 increased. Overexpression of miR-146a directly decreased IRAK1 and TRAF6 expression and attenuated the release of proinflammatory cytokines through the inactivation of NF-κB P65 in hypoxia/reoxygenation (H/R)-induced macrophages, RAW264.7 cells. Knockdown experiments demonstrated that IRAK1 and TRAF6 are two potential targets for reducing the release of proinflammatory cytokines. Moreover, co-culture assays indicated that miR-146a decreases the apoptosis of hepatocytes after H/R. In vivo administration of Ago-miR-146a, a stable version of miR-146a in vivo, protected against liver injury in mice after I/R via inactivation of the TLR signaling pathway. We conclude that miR-146a ameliorates liver ischemia/reperfusion injury in vivo and hypoxia/reoxygenation injury in vitro by directly suppressing IRAK1 and TRAF6.

Characteristic MicroRNA Expression Induced by δ-Opioid Receptor Activation in the Rat Liver Under Prolonged Hypoxia

“…Some studies show that miR-125a-5p prompted the activation and proliferation of hepatic stellate cell by partially down-regulating FIH1 in liver fibrosis [15], and miR-133a-5p was protective against hypoxia/reoxygenation (H/R) injury in vitro by targeting MAPK6 in hepatocytes [56]. Moreover, miR-146a could ameliorate liver hypoxia/reoxygenation injury in vitro by directly suppressing IRAK1 and TRAF6 [12] and miR-494 was protective against hypoxia-induced apoptosis in liver through HIF-1α upregulation by activating PI3K/ Akt pathway [14]. In addition, there is accumulating evidence suggesting that many other miRNAs are involved in liver reactions to hypoxic stress, such as miR-150 downregulation under hypoxia by targeting VEGF-A and HIF1α during liver regeneration [16, 57], miR-192-5p upregulation in hepatocyte injury [13] and increased miR-462/731 cluster in the hypoxia-exposed liver of Megalobrama amblycephala [58] and zebrafish [59].…”

“…There is evidence showing that miR-182 is also downregulated after hypoxia-ischemia brain injury in neonatal rats [65]. Jiang et al reported that miR-146a-5p could ameliorate ischemia/reperfusion injury in vivo and hypoxia/reoxygenation injury in vitro by directly suppressing IRAK1 and TRAF6 in liver [12]. Therefore, it is likely that hypoxia injures the hepatocytes through, at least partially, an inhibitory negative regulation of these two miRNAs, while DOR signaling is able to reverse such negative regulation.…”

“…It has been widely reported that miRNA activity participates in the control of a wide range of biological functions and processes such as hypoxic/ischemic response, tumorigenesis, cell differentiation, and immune regulation [9-11]. For example, miR-146a attenuates hypoxia/reoxygenation injury in vitro by directly suppressing IRAK1 and TRAF6 in liver [12] and miR-192-5p protects liver cell from hepatic injury induced by oxidative stress by targeting Zeb2 [13]. Also, miR-494 protects against hypoxia-induced apoptosis by upregulating HIF1α expression through activating PI3K/Akt pathway [14].…”

Role of miR-148a in Mitigating Hepatic Ischemia-Reperfusion Injury by Repressing the TLR4 Signaling Pathway via Targeting CaMKIIα in Vivo and in Vitro

“…The hypoxia/reoxygenation (H/R) model was created as previous described [20]. Hypoxia preconditioning was performed by culturing cells in a tri-gas incubator with a 1% oxygen concentration according to the manufacturer's instructions.…”

CXCR4 3′UTR functions as a ceRNA in promoting metastasis, proliferation and survival of MCF-7 cells by regulating miR-146a activity

“…Moreover, there is evidence that miR-146a may also target other prometastatic genes in breast cancer, including TNF receptor-associated factor 6 (TRAF6), interleukin-1 receptor-associated kinase (IRAK1), epidermal growth factor receptor (EGFR) and metastasis-associated protein 2 (MTA2) (Bhaumik et al, 2008;Hurst et al, 2009;Li et al, 2010;Hung et al, 2013;Ali et al, 2014;Jiang et al, 2014). According to the newly proposed competing endogenous RNA (ceRNA) hypothesis, specific RNAs targeted by the same groups of miRNAs can regulate one another by competitively binding with microRNAs.…”