Liver ischemia reperfusion (I/R) induces an untoward hyperinflammatory response following partial hepatectomy, liver transplantation, and hypovolemic shock. Currently, there are no effective therapies. While dendritic cells (DCs) are now recognized as the principal mediators of immunity and inflammation throughout the body, our understanding of liver DCs has been rudimentary. During our first 5 years of funding, we primarily established the T cell stimulating capacity of freshly isolated mouse and human liver DCs. In this competitive renewal application for an additional 5 years of funding, we will investigate the innate role of hepatic DCs in liver inflammation. Toll-like receptors (TLRs) are evolutionarily conserved proteins present on immune cells that recognize pathogens, immunologic danger signals and endogenous nucleic acids and subsequently activate innate immunity. We have discovered that TLR9, the intracellular receptor that detects hypomethylated bacterial CpG motifs and endogenous DNA, modulates anti-inflammatory responses by conventional DCs in liver I/R. Additionally, we have discovered that plasmacytoid DCs exert protective effects in I/R. Thus, we hypothesize that endogenous ligands regulate DCs in the immunopathogenesis of liver I/R injury.
In Aim 1, we will determine the regulation of liver I/R by conventional DCs in response to endogenous ligands.
In Aim 2, we will establish the mechanism of protection by plasmacytoid DCs in liver I/R.
In Aim 3, we will establish the TLR requirements for injury in an in vitro model of human liver I/R. The proposed experiments will increase our knowledge regarding the mechanisms of hepatic inflammation. Our investigation has direct relevance to human disease and may lead to the use of TLR blockade for the treatment of hu- man I/R that involves the liver and other organs, such as the heart, kidney, lung, and brain.

Public Health Relevance

In this proposal, we will investigate the role of liver dendritic cells and danger signals released by the host during liver inflammation in mice and humans. Our investigations will be useful in identifying new therapies to treat ischemia reperfusion injury that occurs in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068346-09
Application #
8516021
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
2004-09-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$377,974
Indirect Cost
$179,978
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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