Alcohol Use Disorder affects nearly 20 million individuals in the United States and is a major cause of preventable morbidity and mortality worldwide. Continuous, chronic alcohol abuse underlies the initiation and progression Alcoholic Liver Disease (ALD), attributable to 18,000 deaths in 2013 in the USA. ALD is a spectrum disorder encompassing steatosis, alcoholic hepatitis (AH), cirrhosis and even progressing to liver cancer. The pathogenesis of ALD in humans remains poorly understood and therapeutic options remain unchanged for decades. Despite this, data from human and animal studies demonstrate a robust role for the innate immune system in ALD. Recently, an emerging model of ethanol feeding in mice that resembles early AH in humans has been established. The Chronic/Binge (Gao-Binge or NIAAA model) model of ethanol feeding will establish mechanisms underlying several unknown features of AH, namely marked hepatocellular damage and infiltration of relevant immune cells, such as neutrophils. Macrophage Migration Inhibitory Factor (MIF), a regulator of innate immunity with chemokine- and cytokine-like activities, was previously identified as a key contributor to the early stage of ALD after chronic ethanol feeding to mice. With the advent of an acutely severe model of ethanol feeding, we sought to determine the role of MIF following Chronic/Binge ethanol feeding in mice. Much to our surprise, MIF-deficient mice had increased markers of hepatocellular damage, leukocyte infiltration, and increased inflammatory gene expression in the liver, suggesting that MIF is a hepatoprotective factor in AH. We therefore hypothesized that MIF protects from hepatocellular damage following Chronic/Binge feeding via MIF-mediated suppression of chemokine expression and subsequent leukocyte infiltration into the hepatic parenchyma. To interrogate the precise protective role(s) that MIF is playing in the Chronic/Binge model of ethanol feeding, we will perform loss-of-function and gain-of-function studies with MIF in mice to identify key changes in chemotactic factors, leukocyte infiltration and hepatocellular damage following Chronic/Binge ethanol feeding. Mechanistic studies guided by the results generated in animals will delineate specific, MIF-mediated molecular targets critical to acutely severe ethanol- induced liver injury. The proposed studies could provide rationale for novel therapeutic strategies to treat ALD in humans.
Chronic, excessive consumption of ethanol leads to the progressive degeneration of the liver, known as Alcoholic Liver Disease (ALD). The pathogenesis of ALD is poorly understood and the few therapeutic interventions currently in use are ineffective and unchanged for decades. Our work proposed will use an animal model that closely resembles alcoholic hepatitis in humans, with a focus on the complex web of intercellular communication that recruits immune cells to the liver thought to be critical to ethanol-induced liver damage in humans. Ultimately, therapeutic interventions could be devised from the results of this proposed work to prevent or even reverse the progression of ALD.
| Marin, Veronica; Poulsen, Kyle; Odena, Gemma et al. (2017) Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients. J Hepatol 67:1018-1025 |
