Abstract

In our investigations of liver DC immunobiology relating to our K08 award, we discovered by serendipity two findings which form the basis for our current application. (i) Liver DC are composed of a lipid-rich population and a lipid-poor population, the former of which appears to be pro-inflammatory and the latter of which is tolerogenic, (ii) In NASH, the fraction of lipid-rich DC increases markedly as DC accumulate lipid from their microenvironment. Based on these data we postulate that pro-inflammatory lipid-laden DC play a central role in the hepatitis associated with NASH whereas the lipid-poor DC suppress inflammation and mediate hepatic tolerance.
In Aim 1 we will further evaluate the respective pro-inflammatory and regulatory functions of lipid-rich and lipid-poor DC populations and explore the mechanism for lipid modulation of DC immunogenicity.
In Aim 2 we will test our hypothesis that lipid-rich DC are critical pro-inflammatory effector cells in NASH and evaluate whether modulating DC lipid content is an efficacious approach for experimental therapeutics in NASH.

Public Health Relevance

We postulate the intracellular lipid content dictates liver DC immunogenic or tolerogenic function. Our experiments will test the mechanistic influences of lipids on liver DC capacity to mediate inflammation or immune anergy and investigate the effects of lipid-laden DC on steatohepatitis in NASH.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
5R03DK098303-02
Application #
8617839
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2013-02-15
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$84,750
Indirect Cost
$34,750

  Institution

Name
New York University
Department
Surgery
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016

  Publications

Deutsch, M; Graffeo, C S; Rokosh, R et al. (2015) Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury. Cell Death Dis 6:e1759
Seifert, Lena; Deutsch, Michael; Alothman, Sara et al. (2015) Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways. Cell Rep 13:1909-1921
Rao, Raghavendra; Graffeo, Christopher S; Gulati, Rishabh et al. (2014) Interleukin 17-producing ??T cells promote hepatic regeneration in mice. Gastroenterology 147:473-84.e2
Zambirinis, Constantinos P; Ochi, Atsuo; Barilla, Rocky et al. (2013) Induction of TRIF- or MYD88-dependent pathways perturbs cell cycle regulation in pancreatic cancer. Cell Cycle 12:1153-4