Dendritic cell lipid content effect on hepatic inflammation & NASH pathogenesis

描述（由申请人提供）：在我们与K08奖相关的肝脏DC免疫生物学研究中，我们偶然发现了两个发现，这些发现构成了我们当前申请的基础。(i)肝脏DC由富脂人群和低脂人群组成，前者似乎是促炎的，后者是耐受性的；（ii）在NASH中，富脂DC的比例随着DC从微环境中积累脂质而显著增加。基于这些数据，我们假设促炎脂质负载DC在NASH相关肝炎中起核心作用，而脂质贫乏DC则抑制炎症并介导肝脏耐受。在Aim 1中，我们将进一步评估脂质丰富和脂质贫乏的DC人群各自的促炎和调节功能，并探讨脂质调节DC免疫原性的机制。在Aim 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.