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.
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.
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