Abstract
The Triggering Receptor Expressed on Myeloid cells-like 4 (TREML4) is a member of the TREM receptor family, known modulators of inflammatory responses. We have previously found that TREML4 expression positively correlates with human coronary arterial calcification (CAC). However, the role of TREML4 in the pathogenesis of cardiovascular disease remains incompletely defined. Since macrophages play a key role in inflammatory conditions, we investigated if activated macrophages selectively expressed TREML4 and found that carriage of either one of the eQTL SNP’s previously associated with increased TREML4 expression conferred higher expression in human inflammatory macrophages (M1) compared to alternatively activated macrophages (M2). Furthermore, we found that TREML4 expression in human M1 dysregulated several inflammatory pathways related to leukocyte activation, apoptosis and extracellular matrix degradation. Similarly, murine M1 expressed substantial levels of Treml4, as did oxLDL treated macrophages. Transcriptome analysis confirmed that murine Treml4 controls the expression of genes related to inflammation and lipid regulation pathways, suggesting a possible role in atherosclerosis. Analysis of Apoe–/–/Treml4–/– mice showed reduced plaque burden and lesion complexity as indicated by decreased stage scores, macrophage content and collagen deposition. Finally, transcriptome analysis of oxLDL-loaded murine macrophages showed that Treml4 represses a specific set of genes related to carbohydrate, ion and amino acid membrane transport. Metabolomic analysis confirmed that Treml4 deficiency may promote a beneficial relationship between iron homeostasis and glucose metabolism. Together, our results suggest that Treml4 plays a role in the development of cardiovascular disease, as indicated by Treml4-dependent dysregulation of macrophage inflammatory pathways, macrophage metabolism and promotion of vulnerability features in advanced lesions.
Highlights
Atherosclerosis is a progressive and dynamic disease characterized by low grade inflammation and arterial lipid deposition
An exploratory analysis was performed using isolated peripheral blood monocytes (PBMC’s) from healthy donors of the different haplotypes for both SNP’s and TREML4 expression was examined after macrophage maturation and overnight treatment with either LPS/IFNγ (M1) or IL4 (M2) (Figure 1A)
We investigated whether TREML4 expression directly affected M1 polarization markers by qPCR and found that TREML4 expression does not affect upregulation of TNF or IRG1 or the correspondent downregulation of MRC1 in M1 macrophages (Figure 1B)
Summary
Atherosclerosis is a progressive and dynamic disease characterized by low grade inflammation and arterial lipid deposition. Human atherosclerosis can be practically divided into several stages which has aided in characterizing critical modulators and risk factors [2, 3]. The molecular mechanisms of atherosclerotic complications remain obscure, despite advances in modeling disease and unraveling factors in its progression, predominantly through the use of animal models. Traditional GWAS studies and similar approaches have, far, met with limited success in identifying genes and pathways relevant to advanced atherosclerosis, leaving the underlying causes of disease complications largely elusive [4,5,6,7,8]. By using an integrated multiomics and functional approach, our group identified expression of the Triggering Receptor Expressed on Myeloid cells (TREM)-like 4 (TREML4) to be strongly correlated with Coronary Arterial Calcification (CAC) [9]. While CAC and similar conditions are recognized as strong predictors for future cardiovascular events, it remains unclear whether they will predict plaque instability or correlate with plaque burden [3]
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