Effect of dendritic cell lipid content on hepatic inflammation and NASH pathogene

描述(申请人提供)：在我们与K08奖项相关的肝脏DC免疫生物学调查中，我们偶然发现了两个发现，这两个发现构成了我们目前申请的基础。(I)肝脏DC由富脂人群和贫脂人群组成，前者似乎是促炎的，后者是耐受性的；(Ii)在NASH中，随着DC从其微环境中积累脂质，富脂DC的比例显著增加。基于这些数据，我们推测，在NASH相关的肝炎中，致炎的载脂DC起核心作用，而载脂的DC抑制炎症并调节肝耐受。在目标1中，我们将进一步评估富脂和贫脂DC群体各自的促炎和调节功能，并探讨DC免疫原性的脂质调节机制。在目标2中，我们将验证我们的假设，即富含脂质的DC是NASH中关键的促炎效应细胞，并评估调节DC脂质含量是否是NASH实验治疗的有效方法。

DESCRIPTION (provided by applicant): 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.