Th223 - Role of Microrna-mediated Macrophage Polarization in Immune Response During Cholestatic Liver Injury

Ying Wan, Ph.D – Professor, Pathophysiology, Southwest Medical University, Luzhou, Sichuan, China; Jennifer Salinas – Indiana University School of Medicine; Wenjuan Xu – Indiana University School of Medicine; Sugeily Lorenzo – Baylor Scott & White Hospital; bingru Zhou – Southwest Medical University, Luzhou, Sichuan, China; Elise Slevin – Indiana University School of Medicine

Abstract Text: Macrophages are important components of innate and adaptive immunity that are highly heterogeneous and plastic. Primary sclerosing cholangitis (PSC) is chronic liver diseases characterized with immune responses, inflammation and fibrotic scar formation which would ultimately lead to choleostasis. The current study aimed to clarify the role of liver specific microRNA in choleostasis associated macrophage polarization, immune response and liver fibrosis. A liver specific miR-34a knockout mouse was established by crossing floxed miR-34a mice with the albumin cre mice, and subjected to bile duct ligation surgery relative to controls. Bile duct ligation surgery induced liver injuries which include necrosis, fibrosis, and immune cell infiltration. Interestingly, liver specific miR-34a knockout significantly alleviates liver damages which may be due to decreased biliary ductular reactions associated with immune response and liver fibrosis. It was found that miR-34a-mediated ductular reactions are possibly through Sirt-1-mediated immune response and fibrosis. Furthermore, hepatocyte-derived miR-34a regulates LPS-induced immune response and fibrotic response likely through paracrine effects. Enhanced expression of macrophage M1 markers, CD86 and TNFα was observed in BDL WT mice, which was significantly reduced in BDL miR-34a liver specific KO mice. On the other hand, M2 markers including arginase1 and FIZZ 1, was decreased in BDL WT mice, but recovered after the depletion of miR-34a. These data provide strong evidence that macrophages in the context of immune response and hepatic fibrosis exhibit miR-34a regulated M1/M2 polarization. The current study demonstrates that liver specific miR-34a plays a deleterious role in macrophage polarization, immune response and liver fibrosis during cholestasis.