162 - Haematopoetic TREM2 deficiency modulates atherosclerosis and lipid metabolism (ID 839)
Abstract
Background and Aims
Triggering receptor expressed on myeloid cells 2 (TREM2) is a lipid-sensing receptor involved in the regulation of several key myeloid cell functions, including proliferation, survival and phagocytosis. TREM2 is highly expressed on a subset of atherosclerosis-associated aortic macrophages, which express genes associated with lipid metabolism, oxidative stress and calcification while downregulating pro-inflammatory genes. These macrophages correspond to foamy macrophages, which are important players in atherogenesis. Therefore, we sought to investigate the effect of TREM2 deficiency on atherosclerosis.
Methods
Male Ldlr-/- mice were lethally irradiated and received Trem2-/- or Trem2+/+ bone marrow. After 12 weeks on Western diet, atherosclerotic lesion size, immune cell composition, plasma and hepatic lipid levels were assessed, and aortas were subjected to single cell sequencing. Additionally, foam cell formation was measured in vitro.
Results
Mice with haematopoietic TREM2 deficiency showed significantly larger atherosclerotic plaques compared to controls. Single cell sequencing revealed aortic plaques to be highly enriched in T cells. Additionally, TREM2 deficiency led to hepatosplenomegaly and an accumulation of neutrophils as well as Ly6Chigh and Ly6Clow monocytes in the spleen and liver, while splenic T cells showed increased activation. Furthermore, TREM2-deficient mice developed elevated plasma and hepatic cholesterol and triglyceride levels. In vitro, thioglycollate-elicited peritoneal macrophages from Trem2-/- mice showed reduced lipid content following incubation with CuOx-LDL compared to controls, indicative of reduced foam cell formation.
Conclusions
Our data show that haematopoietic TREM2 modulates atherosclerosis development and plays a role in the regulation of inflammation, T cell activation as well as in lipid metabolism and foam cell formation.
