Circulating extracellular vesicle-encapsulated microRNA-557 induces a proinflammatory immune response and serves as a diagnostic or relapse marker in autoimmune hepatitis.

Abstract

This study investigated serum microRNAs (miRNAs/miRs) in autoimmune hepatitis (AIH) and the relationship of these molecules with diagnostic and relapse markers. Initially, extracellular vesicle-encapsulated miRNAs (EV-miRNAs) in serum with altered expression in AIH relative to healthy control (HC) samples were identified using microarray analysis. To validate the microarray results, the expression levels of selected EV-miRNAs were determined. Among the 2569 mature miRNAs evaluated in the microarray, EV-miR-557 discriminated patients with AIH from healthy controls (HCs). Validation by digital polymerase chain reaction indicated that serum EV-miR-557 levels were higher in patients with AIH (7.75 copies/μl) than in patients with non-alcoholic steatohepatitis (1.60 copies/μl; p<0.001), patients with primary biliary cholangitis (2.16 copies/μl; p<0.005), and HCs (1.86 copies/μl; p<0.005). The area under the receiver operating characteristic curve values for the probability of AIH using serum EV-miR-557 between the AIH and non-alcoholic steatohepatitis, AIH and primary biliary cholangitis, and AIH and HC groups were 0.81, 0.78, and 0.79, respectively. In addition, serum EV-miR-557 levels >7.69 copies/μl were associated with a significantly higher risk of relapse in patients with AIH (7-year incidence rate: 11.1 vs. 35.4%, log-rank test, p<0.05). Interestingly, gene expression analysis revealed that increased miR-557 expression following transient transfection of peripheral blood mononuclear cells with a miR-557 mimic resulted in enhanced expression of proinflammatory cytokine-related genes such as interleukin-6, interferon-γ, and tumor necrosis factor. Moreover, miR-557 induced significant tumor necrosis factor-α production (mean: 313.5 vs. 10642.3 pg/ml, p<0.05). EV-miR-557 may play an important role as a potential biomarker of AIH and may be a promising therapeutic target for AIH.