A critical barrier to progress in the field of alcoholic liver disease (ALD) is the lack of knowledge on the key proinflammatory mediators and the mechanisms whereby they drive liver injury. High-mobility group box-1 (HMGB1) is a damage-associated molecular pattern that communicates and amplifies inflammation to neighboring cells. Preliminary studies supporting this application reveal that HMGB1 increases, undergoes post- translational modifications and is secreted in alcoholic patients and mouse models of ALD. We identified that both hepatocytes and Kupffer cells produce fully reduced and acetylated HMGB1 whereas hepatocytes are the main source of oxidized HMGB1. We show that conditional ablation of Hmgb1 in hepatocytes or myeloid cells partially protects while deletion in both prevents inflammation, interleukin-1? (IL1?) production and ALD. Likewise, knockdown of the HMGB1 receptor for advanced glycation end-products (RAGE) in myeloid cells protects from ALD. We have identified that oxidized HMGB1 forms a complex with IL1? in alcoholic patients and in mice. Overall, HMGB1 drives immune cell infiltration, activates NF?B and increases the proinflammatory cytokine IL1?, all central events for the onset and progression of ALD. While the HMGB1 isoforms appear to have distinct effects; yet, the precise contribution of each one of them to alcohol-induced inflammation and IL1? production remains undefined. We believe that the levels of acetylated and oxidized HMGB1 regulate inflammatory cell infiltration upon alcohol exposure. These isoforms may also drive the expression of the key NF?B target proinflammatory cytokine IL1?. Since oxidized HMGB1 forms a complex with IL1?, it could be immunostimulatory and enhance RAGE and/or IL1R signaling. This may be particularly relevant as both molecules are central to the pathogenesis of ALD. Yet, further understanding is needed on how the isoforms lead to immune cell infiltration, the key receptor involved, their binding affinity and if they signal per se or via immunostimulatory complexes with IL1? to drive NF?B induction of Il1? mRNA and ultimately maturation of IL1? protein in ALD. Our central hypothesis is that the levels of acetylated and oxidized HMGB1 regulate inflammatory cell infiltration and IL1? production in ALD.
Two specific aims are planned to prove this hypothesis.
In Aim 1, we will dissect how the alcohol-mediated increase in the HMGB1 isoforms regulates inflammatory cell infiltration into the liver.
In Aim 2, we will determine the receptor binding affinity of the HMGB1 isoforms and if they signal per se or form immunostimulatory complexes with IL1? to drive NF?B induction of Il1? mRNA and maturation of IL1? protein in ALD. Our long-term goal is to dissect the pathogenic role of the HMGB1 isoforms as potential therapeutic targets to prevent ALD.

Public Health Relevance

To date, there is no proven effective cure for alcoholic liver disease. We have recently identified that high- mobility group box-1 is a protein increased during alcohol-induced liver injury and undergoes unique post- translational modifications; yet, their mechanism of action is still unknown. The work proposed in this application will reveal how the isoforms of this protein participate in the pathogenesis of alcohol-induced liver injury by regulating inmune cell infiltration and the production of the proinflammatory cytokine IL1?. The results from this project will contribute to design new therapies for preventing or treating alcoholic liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA025907-01A1
Application #
9519281
Study Section
National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
Program Officer
Wang, Joe
Project Start
2018-07-06
Project End
2023-06-30
Budget Start
2018-07-06
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612