Enoxacin Up-Regulates MicroRNA Biogenesis and Down-Regulates Cytotoxic CD8 T-Cell Function in Autoimmune Cholangitis.

Abstract

BACKGROUND AND AIMS:

Primary biliary cholangitis (PBC) is a prototypical organ-specific autoimmune disease that is mediated by autoreactive T-cell attack and destruction of cholangiocytes. Despite the clear role of autoimmunity in PBC, immune-directed therapies have failed to halt PBC, including biologic therapies effective in other autoimmune diseases. MicroRNA (miRNA) dysregulation is implicated in the pathogenesis (PBC). In the dominant-negative TGF-β receptor type II (dnTGFβRII) mouse model of PBC, autoreactive CD8 T cells play a major pathogenic role and demonstrate a striking pattern of miRNA down-regulation. Enoxacin is a small molecule fluoroquinolone that enhances miRNA biogenesis, partly by stabilizing the interaction of transactivation response RNA-binding protein with Argonaute (Ago) 2.

APPROACH AND RESULTS:

We hypothesized that correcting aberrant T-cell miRNA expression with enoxacin in dnTGFβRII mice could modulate autoreactive T-cell function and prevent PBC. Here, we show that liver-infiltrating dnTGFβRII CD8 T cells have significantly decreased levels of the miRNA biogenesis molecules prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and Ago2 along with significantly increased levels of granzyme B and perforin. Enoxacin treatment significantly up-regulated miRNAs in dnTGFβRII CD8 T cells and effectively treated autoimmune cholangitis in dnTGFβRII mice. Enoxacin treatment directly altered T cells both ex vivo and in vitro, resulting in altered memory subset numbers, decreased proliferation, and decreased interferon-γ production. Enoxacin significantly decreased CD8 T-cell expression of the transcription factor, Runx3, and significantly decreased perforin expression at both the mRNA and protein levels.

CONCLUSIONS:

Enoxacin increases miRNA expression in dnTGFβRII CD8 T cells, reduces CD8 T-cell pathogenicity, and effectively halted progression of autoimmune biliary disease. Targeting the miRNA pathway is a therapeutic approach to autoimmunity that corrects pathological miRNA abnormalities in autoreactive T cells.

• Authors: Arata Itoh, David Adams, Wenting Huang, Yuehong Wu, Kritika Kachapati, Kyle J Bednar, Patrick S C Leung, Weici Zhang, Richard A Flavell, M Eric Gershwin, William M Ridgway
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 74 Issue 2 Pg. 835-846 (08 2021) ISSN: 1527-3350 [Electronic] United States
• PMID: 33462854 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

Chemical References

• MicroRNAs
• Enoxacin

Topics

• Animals
• Autoimmune Diseases (drug therapy, genetics, immunology)
• Cells, Cultured
• Disease Models, Animal
• Enoxacin (pharmacology, therapeutic use)
• Humans
• Liver Cirrhosis, Biliary (drug therapy, genetics, immunology)
• Mice
• MicroRNAs (biosynthesis)
• Primary Cell Culture
• T-Lymphocytes, Cytotoxic (drug effects, immunology, metabolism)
• Up-Regulation (drug effects, immunology)