Abstract 17: Apolipoprotein C-III Promotes Anti-Inflammatory Regulatory T Cell Phenotype Through Modulation of Intestinal Dendritic Cell Activation

Abstract

Apolipoprotein C-III (apoC-III) is a cardio-metabolic modulator in multiple tissues. Circulating apoC-III in humans is an independent risk factor for cardiovascular disease (CVD) because apoC-III increases circulating triglyceride (TG) through inhibition of the LDLR in the liver and lipoprotein lipase on the capillary endothelium. In the liver, apoC-III overexpression results in increased synthesis and secretion of more TG-rich VLDL. These actions increase the resident time and amount of atherogenic remnants in circulation. Paradoxically, apoC-III acts in the intestine to inhibit dietary fat absorption, a potentially beneficial action. Using human-apoC-III transgenic mice (hu-apoCIII tg mice), which have increased circulating TG compared to C57Bl6/J littermate controls (WT), we have identified an increase in circulating IL-10 at basal conditions. Regulatory T cells (Tregs), a T cell subset that is known to delay atheroprogression, secrete the anti-inflammatory cytokine IL-10. Knowing that the immune system plays a dynamic role in atherogenesis, we asked whether apoC-III is a potential modulator of Tregs during a western diet (WD) challenge. We subjected hu-apoCIII tg and WT mice to 12 weeks of a WD and through flow cytometry, found significantly increased circulating and intestinal Tregs in hu-apoCIII tg mice compared to WT. Hu-apoCIII tg intestinal gene expression showed increases in TGF-β and maintenance of IL-10 and FOXP3, key Treg-related genes, after the WD compared to WT. We hypothesized that apoC-III may act in the intestine to induce tolerance to dietary antigens through dendritic cell (DC) activation and subsequent differentiation of naïve T cells to the Treg phenotype. Using flow cytometry of the lamina propria, we saw increased activation of intestinal DCs, in hu-apoCIII tg mice at basal and WD-challenged conditions suggesting that intestinal DCs are influenced by apoC-III overexpression. These results suggest that apoC-III may influence Treg differentiation or proliferation through alteration of intestinal DC activation. The phenotype we have uncovered in hu-apoC-III tg mice suggests a link between apoC-III overexpression, dietary fat absorption, and the immune system, and that this may be protective against inflammation.