Expression of microRNA-155 in inflammatory cells modulates liver injury

ABSTRACT

miR-155 is involved in immune and inflammatory diseases and is associated with liver fibrosis and steatohepatitis. However, the mechanisms involved in miR-155 regulation of liver injury are largely unknown. The role of miR-155 in acute liver injury was assessed in wild type (WT), miR-155^-/- and miR-155^-/- mice transplanted with WT bone marrow. Additionally, miR-155 expression was evaluated in liver tissue and peripheral blood mononuclear cells (PBMC) of patients with autoimmune hepatitis. Concanavalin A (ConA) but not acetaminophen (APAP) treatment increased the expression of miR-155 in liver tissue of WT mice. ConA induced an increase of cell death, liver transaminases and a higher expression of pro-inflammatory cytokines (Cxcl1, 5, 9, 10, 11, Ccl2, 20 and Icam1) in miR-155^-/- compared to WT mice. Importantly, these animals showed a significant decrease in CD4⁺CXCR3⁺ and Foxp3⁺ cells recruitment but no changes in other inflammatory cell populations. Mechanistically, miR-155 deficient Tregs showed increased Ship1 expression, a known target of miR-155. Inhibition of Ship1 in miR-155^-/- mice restored Foxp3 recruitment and reduced liver cytokine expression. Transplantation of bone marrow from WT animals into miR-155^-/- mice partially reverted the effect of ConA on miR-155^-/- mice as assessed by proinflammatory cytokines and cell death protein expression. Patients with autoimmune hepatitis showed a marked increase in miR-155 expression in the liver but a reduced expression of miR-155 in PBMC. Conclusions: miR-155 expression is altered in both liver tissue and circulating inflammatory cells during liver injury, thus regulating inflammatory cell recruitment and liver damage. These results suggest that maintaining miR-155 expression in inflammatory cells might be a potential strategy to modulate liver injury. This article is protected by copyright. All rights reserved.

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