miR-449a ameliorates acute rejection after liver transplantation via targeting procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 in macrophages.

Acute rejection (AR) is an important factor that leads to poor prognosis after liver transplantation (LT). Macrophage M1-polarization is an important mechanism in AR development. MicroRNAs play vital roles in disease regulation; however, their effects on macrophages and AR remain unclear. In this study, rat models of AR were established following LT, and macrophages and peripheral blood mononuclear cells were isolated from rats and humans, respectively. We found miR-449a expression to be significantly reduced in macrophages and peripheral blood mononuclear cells. Overexpression of miR-449a not only inhibited the M1-polarization of macrophages in vitro but also improved the AR of transplant in vivo. The mechanism involved inhibiting the noncanonical nuclear factor-kappaB (NF-κB) pathway. We identified procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 (PLOD1) as a target gene of miR-449a, which could reverse miR-449a's inhibition of macrophage M1-polarization, amelioration of AR, and inhibition of the NF-κB pathway. Overall, miR-449a inhibited the NF-κB pathway in macrophages through PLOD1 and also inhibited the M1-polarization of macrophages, thus attenuating AR after LT. In conclusion, miR-449a and PLOD1 may be new targets for the prevention and mitigation of AR.

miR-194 ameliorates hepatic ischemia/reperfusion injury via targeting PHLDA1 in a TRAF6-dependent manner.

Hepatic ischemia/reperfusion injury (IRI) is an inevitable pathological process in liver resection, shock and transplantation. However, the internal mechanism of hepatic IRI, including inflammatory transduction of multiple signaling pathways, is not fully understood. In the present study, we identified pleckstrin homology-like domain family member 1 (PHLDA1), suppressed by microRNA (miR)-194, as a critical intersection of dual inflammatory signals in hepatic IRI. PHLDA1 was upregulated in hepatic IRI with a concomitant downregulation of miR-194. Overexpression of miR-194 diminished PHLDA1 and inhibitors of the nuclear factor kappa-B kinase (IKK) pathway, thus leading to remission of hepatic pathological injury, apoptosis and release of cytokines. Further enrichment of PHLDA1 reversed the function of miR-194 both in vivo and in vitro. For an in-depth query, we verified PHLDA1 as a direct target of miR-194. Notably, inflammatory signal transduction of PHLDA1 was induced by activating TNF receptor-associated factor 6 (TRAF6), sequentially initiating IKK and mitogen-activated protein kinase (MAPK), both of which aggravate stress and inflammation in hepatic IRI. In conclusion, the miR-194/PHLDA1 axis was a key upstream regulator of IKK and MAPK in hepatic IRI. Targeting PHLDA1 might be a potential strategy for hepatic IRI therapy.