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

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‐7def 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.