Document Type

Conference Proceeding

Publication Date

10-2023

Publication Title

Hepatology

Abstract

Background: The underlying mechanism contributing to cholestatic liver injury remains unclear. The proinflammatory cytokine interleukin-17A (IL-17A) has been implicated in human cholestatic liver injury. However, mechanistic insights on how IL-17A modulates cholestatic liver injury are lacking and require further exploration in preclinical models. Herein, we examined the effects of IL-17A genetic deletion in a mouse model of cholestasis. Methods: Ageand gender-matched littermate WT and Il-17a-/- were fed intermittently on 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet or control diet (n=10, each) and standard diet for 21 days to induce cholestatic liver injury. We assessed liver inflammation, ductular reaction, and fibrosis using complementary approaches. Results: DDC-fed mice displayed significant increases in liver weight/body weight ratio and histological and serological characteristics of cholestatic liver injury compared to control-diet-fed mice in both WT and Il-17a-/- mice; however, there were no differences between WT and Il- 17a-/- DDC-fed mice. Immunofluorescence staining for Desmin and Collagen I and Sirius red indicated portal fibrosis was significantly increased in DDC-fed Il-17a-/- mice compared to DDC-fed WT mice. Immunofluorescence staining for IBA1 (a pan macrophage marker) and myeloperoxidase (a neutrophil marker) displayed an increase in macrophages and neutrophils in DDC-fed Il-17a-/- mice vs. DDC-fed WT mice. Mass cytometry (CyTOF) on intrahepatic leukocytes confirmed this observation. Gene expression profiling and pathway analysis of intrahepatic leukocytes subjected to Nanostring analysis displayed upregulation of multiple profibrogenic genes and enrichment of fibrosis-relating pathways in both WT and Il-17a-/- mice. Compared to DDC-fed WT mice, the profibrotic gene Tnfsf14 was significantly upregulated in DDC-fed Il-17a-/- mice. Taken together, these data suggest deletion of Il-17a in the mouse model of cholestatic liver injury results in upregulating profibrogenic pathways and alteration of immune cell populations within the liver, promoting fibrosis. Conclusion: IL-17A appears to restrain liver inflammation and fibrosis by suppressing Tnfsf14 expression.

Volume

78

Issue

S1

First Page

S1787

Comments

American Association for the Study of Liver Diseases AASLD, The Liver Meeting, November 10-14, 2023, Boston, MA

DOI

10.1097/HEP.0000000000000580

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