Abstract 51: Parasitic Soluble Egg Antigens Fight Atherosclerosis from 2 Different Angles

Abstract

With intra-plaque inflammation being a major hallmark of atherosclerotic lesion growth and instability, modulation of the immune system may yield therapeutic potential in combating atherosclerosis. Helminths and their derivatives have immune modulating properties and are known for their anti-inflammatory effects. We investigated if immune modulation by Soluble Egg Antigens (SEA) derived from the helminth Schistosoma Mansoni can affect macrophage function and protect against atherosclerosis. In vitro , primary macrophages skewed by SEA showed an anti-inflammatory M2 phenotype. SEA induced the production of IL-10, an anti-inflammatory cytokine with known anti-atherogenic capacities, while inhibiting LPS-induced production of pro-inflammatory mediators. Likewise, peritoneal macrophages isolated from SEA-treated mice showed increased IL-10 production, thereby confirming the M2 macrophage-inducing potential of SEA in vivo . Additionally, T-lymphocytes showed a profound T H 2 polarization after SEA treatment in vivo . To study the effect of SEA treatment on atherosclerosis, LDLR -/- mice (n=20) were weekly injected with SEA or vehicle before and during 9 weeks of high fat feeding. Examination of the aortic root showed a 44% decrease in plaque size by SEA treatment (386.2x10 3 μm 2 ± 159.3 vs. 214.3x10 3 μm 2 ± 58.7, p<0.0001) along with less advanced lesions compared to controls. Furthermore, pathological assessment revealed smaller necrotic cores and less monocyte adhesion in lesions from SEA-treated mice. Besides an additional lowering of plasma cholesterol (45.17 mM ± 6.1 vs. 36.99 mM ± 4.28, p<0.0001), SEA reduced high fat diet-induced leukocytosis (9900.6 cells/μl μm 2 ± 2503.6 vs. 7535.11x10 3 μm 2 ± 1892.1, p<0.05), in particular at the myeloid level. Interestingly, both blood monocytes and isolated peritoneal macrophages pointed towards an anti-inflammatory phenotype by SEA, characterized by less Ly6C high cells and increased IL-10 production respectively. Finally, peritoneal macrophages from SEA-treated mice showed less lipid accumulation . In conclusion, SEA have the potential to reduce atherosclerosis from 2 perspectives: lowering plasma cholesterol levels and dampening the inflammatory (myeloid) immune status.