C/EBPα/miR‐7 Controls CD4+ T‐Cell Activation and Function and Orchestrates Experimental Autoimmune Hepatitis in Mice

Abstract

BaCKgRoUND aND aIMS:Increasing evidence in recent years has suggested that microRNA-7 (miR-7) is an important gene implicated in the development of various diseases including HCC. However, the role of miR-7 in autoimmune hepatitis (AIH) is unknown. appRoaCH aND ReSUltS: Herein, we showed that miR-7 deficiency led to exacerbated pathology in Concanavalin-A-induced murine acute autoimmune liver injury (ALI) model, accompanied by hyperactivation state of CD4 + T cells. Depletion of CD4 + T cells reduced the effect of miR-7 deficiency on the pathology of ALI. Interestingly, miR-7 deficiency elevated CD4 + T-cell activation, proliferation, and cytokine production in vitro. Adoptive cell transfer experiments showed that miR-7 def CD4 + T cells could exacerbate the pathology of ALI. Further analysis showed that miR-7 expression was up-regulated in activated CD4 + T cells. Importantly, the transcription of pre-miR-7b, a major resource of mature miR-7 in CD4 + T cells, was dominantly dependent on transcription factor CCAAT enhancer binding protein alpha (C/ EBPα), which binds to the core promoter region of the miR-7b gene. Global gene analysis showed that mitogen-activated protein kinase 4 (MAPK4) is a target of miR-7 in CD4 + T cells. Finally, the loss of MAPK4 could ameliorate the activation state of CD4 + T cells with or without miR-7 deficiency.Our studies document the important role of miR-7 in the setting of AIH induced by Concanavalin-A. Specifically, we provide evidence that the C/EBPα/miR-7 axis negatively controls CD4 + T-cell activation and function through MAPK4, thereby orchestrating experimental AIH in mice.CoNClUSIoNS: This study expands on the important role of miR-7 in liver-related diseases and reveals the value of the C/EBPα/miR-7 axis in CD4 + T-cell biological function for the pathogenesis of immune-mediated liver diseases.

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