GSBS Dissertations and Theses

ORCID ID

0000-0002-6635-3904

Publication Date

2017-11-01

Document Type

Doctoral Dissertation

Academic Program

Translational Science

Department

Department of Medicine

First Thesis Advisor

Gyongyi Szabo, MD, PhD

Keywords

Alcoholic liver disease, NLRP3 inflammasome, apoptosis, interferon regulatory factor 3, stimulator of interferon genes, unfolded protein response, anakinra

Abstract

Central driving forces in the pathogenesis of liver disease are hepatocyte death and immune cell-driven inflammation. The interplay between outcomes, stemming from these two major cell types, is present from the earliest ethanol exposure, and are both determinants in advanced stages of liver disease particularly in alcoholic liver disease (ALD). The complexities associated with advanced ALD are many and therapies are limited. Due to the liver’s role in ethanol metabolism and filtering gut-derived products, it is becoming increasingly clear that innate immunity plays a central role in triggering activation of cell death and inflammatory pathways in ALD. We identified interferon regulatory factor 3 (IRF3) activation as a mediator of hepatocyte death as the first event after ethanol exposure, and the inflammasome as a protein complex responsible for the subsequent inflammatory cascade, driven by the NLRP3 inflammasome.

Our novel findings in murine samples and human patients with alcoholic hepatitis demonstrate that ethanol-induced inflammasome activity results in Caspase-1-mediated pyroptosis and extracellular ASC aggregates in the liver and circulation. Pyroptosis can be abrogated by therapeutic inhibition of inflammasome components, NLRP3 or Caspase-1. Taken together, the event leading to mtDNA release into the cytoplasm is the inception of the pathogenesis of ALD, triggering hepatocyte death, culminating in a pro-inflammatory cascade driven by the NLRP3 inflammasome and pyroptotic release of ASC.

DOI

10.13028/M2K674

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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