MiR-122 regulates liver tolerance

The liver is an immune privileged organ, yet it needs to overcome infections. We aimed to explore the role of the liver-specific microRNA miR-122 in liver immune tolerance.

We developed a miR-122 knockout (KO) mouse model and assessed immune, inflammatory, and fibrogenic responses from early postnatal stages. Innate and adaptive immune alterations were studied in miR-122 KO mice. Transcriptomic profiles from autoimmune hepatitis (AIH) patients were compared to these KO mice.

MiR-122 KO mice developed liver inflammation and fibrosis as early as two weeks of age. An inverse correlation between miR-122 expression and inflammation/fibrosis was observed in both KO mice (p<0.01in both at weeks two (n=6) and three (n=6) of KO mice age) and human AIH samples (p<0.01, n=9). KO mice shared transcriptomic and phenotypic features with human AIH. RNA sequencing identified over 5,000 differentially expressed genes between wt and KO mice, including upregulated chemokines, immune checkpoints, and pro-fibrotic markers. IRF2, a TLR3 transcription factor, was identified as a novel direct target of miR-122.

MiR-122 is a key regulator of liver immune tolerance, modulating inflammation and fibrosis via distinct pathways. Its absence enhances immune activation and accelerates fibrosis. These findings identify miR-122 as a promising therapeutic target for autoimmune liver diseases.

The liver is an immune-privileged organ, an adaptation likely evolved to prevent robust immune responses against material absorbed from the gastrointestinal tract. This tolerance creates a sanctuary for pathogens-including bacteria, hepatitis viruses, and parasites such as Plasmodium-within the liver parenchyma, and similarly permits the development of primary liver malignancy and metastatic seeding. We found that miR-122 regulates hepatic immune tolerance, positioning miR-122 modulation as a potential therapeutic strategy for infectious, autoimmune, malignant, and metastatic liver diseases.