MiR-122 regulates liver tolerance.
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Gefen Maytal, Layani Shanny, Klahr Emma, Shemuelian Zohar, Brandi Johannes, Jacobs Thomas, Steeg Christiane, Adlung Lorenz, Kilian Christoph, Ordan Merav, Gordon Oren, Abudi Nathalie, Abramovitch Rinat, Nevo Yuval, Elgavish Sharona, Benyamini Hadar, Monin Jonathan, Khvalevsky Elina Zorde, Rosenberg Nofar, Markezana Aurelia, Yaish Dayana, Yehezkel Adi S, Simerzin Alina, Rivkin Mila, Amran Osher, Goldenberg Daniel S, Peled Amnon, Axelrod Jonathan, Rachmilewitz Jacob, Huber Samuel, Gagliani Nicola, Schramm Christoph, Weidemann Sören, Herkel Johannes, Carambia Antonella, Safadi Rifaat, Khalaileh Abed, Imam Ashraf, Heide Daniela, Hetzer Jenny, Rose-John Stefan, Heikenwälder Mathias, Giladi Hilla, Galun Eithan
Аннотация
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
IMPACT AND IMPLICATION: 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.