Linking risk factors for atherosclerosis development to triggering receptor expressed on myeloid cells 2 - mediated foam cell formation

Abstract Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) signaling interacts with inflammatory pathways, but its relationship with the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in atherosclerosis (ATHSCL) is unclear. TREM2 is crucial for lipid metabolism, foam cell formation, and macrophage cells (Mc) function within atherosclerotic plaques. Its role can be both pro- and anti-atherogenic. TREM2 exists in transmembrane and in soluble form, both play roles in immune regulation. Exposure to soluble bacterial components trigger systemic inflammation by activating the NLRP3, which amplifies these pathways and accelerates ATHSCL progression. Hypercholesterolemia, arterial hypertension (HA), diabetes mellitus type 2 (DM), age and sex impact disease progression. Aim: to investigate how NLRP3 activation, as reflected in TREM2 tissue expression and the serum concentration of its soluble form (sTREM2), contributes to foam cell formation and the progression of ATHSCL. Methods: The study analyzed serum and aortic tissue from 8 bypass surgery patients (pts), along with monocytes from THP-1 wild-type and NLRP3-knockout (THPKONLRP3) cell lines. Microscopic analysis evaluated Mc presence and TREM2 expression, while serum tests measured sTREM2 levels. Macrophage-to-foam cell transformation was assessed. Results: THP1 macrophages exposed to H. pylori (HP) or E. coli (EC) endotoxins, in presence of 7-ketocholesterol (7KCh), demonstrate activation of the NLRP3 inflammasome (Fig. A). As a result of exposure to infectious agents and 7KCh, a decrease in percentage of foam cells was observed among NLRP3-knockout cells compared to control THP1 cells (Fig. B). Activation of NLRP3 inflammasome in Mc results in decrease of surface expression of TREM2 receptors (Fig. C), indicating their release as sTREM2. Results indicate that pts exhibit four distinct types (T) of balance in expression of TREM2 and sTREM2. T1 - no TREM2 on Mc in aortic tissue and no detectable sTREM2 in serum. T2 - TREM2 confirmed on Mc , but no sTREM2 - in serum. T3 - TREM2 on Mc, with sTREM2 in serum. T4 - No TREM2 on Mc, but the sTREM2 present in serum. According to the literature, T1 and 2 exhibit an early ATHSCL profile, while T3 and 4 - an advanced profile. An analysis of prevalence of risk factors — specifically age above 60 years (60+), male sex, hypercholesterolemia, HA and DM revealed that: for patients with T1 and 2, the fraction of pts 60+ was 0,5, for male sex 0,75, for HA - 0.5, for hypercholesterolemia - 0.25, and for DM - 0.25. In contrast, for patients with T3 and 4, the values were 0,75; 0,75, all (1); 0.25 and 0.5 respectively. Conclusions: The search for new biomarkers - such as transmembrane TREM2 on macrophage cells / sTREM2 in serum balance - appears to be an accurate marker of the degree of atherosclerosis. Using that criterion the pts who qualified for bypass surgery in our study were at different stages of progression of atherosclerosis.Figure A and Figure B Figure Carrow shows lipid bodies