Figure 8: Model for multilayered pathogenic roles of TREM-1 in diet-induced atherogenesis.
From: TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis
(1) TREM-1 skews myeloid differentiation towards increased monocyte output by yet undetermined direct or indirect mechanisms, likely acting together with microbial or dietary PAMPs which become systemically available following HFCD feeding. (2) These factors may also be involved on the upregulation of TREM-1 on peripheral blood myeloid cell subsets. (3) TREM-1 is further upregulated on Ly6Chi monocytes following their transmigration to the intima and exposure to oxLDL. (4) Activation of monocytes via TREM-1 may be mediated by neutrophil-derived PGLYRP1 (not depicted) or by HMGB1 released by activated or necrotic macrophages. (5) TREM-1-mediated activation promotes the expression of scavenger receptors CD36, MSR1 and the LDLR and thereby increases lipid uptake. TREM-1 further promotes foam cell formation by interfering with intracellular cholesterol transport and efflux mechanisms (not depicted). (6) CD36 facilitates TLR4/6 assembly and NLRP3 activation (not depicted) leading to increased pro-inflammatory cytokine and ROS production, which may contribute to additional lipid peroxidation. Concurring TREM-1-mediated activation could further amplify these pro-inflammatory processes. (7) Increased uptake of oxLDL leads to the differentiation of Ly6Chi monocytes to Ly6C− macrophage foam cells through a Ly6Cint TREM-1+ MHCII+ intermediary stage.
