TREML4 Promotes Inflammatory Programs in Human and Murine Macrophages and Alters Atherosclerosis Lesion Composition in the Apolipoprotein E Deficient Mouse

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 <i>TREML4</i> expression positively correlates with human coronary arterial calcification (CAC). However, the role of <i>TREML4</i> 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 <i>TREML4</i> and found that carriage of either one of the eQTL SNP's previously associated with increased <i>TREML4</i> expression conferred higher expression in human inflammatory macrophages (M1) compared to alternatively activated macrophages (M2). Furthermore, we found that <i>TREML4</i> expression in human M1 dysregulated several inflammatory pathways related to leukocyte activation, apoptosis and extracellular matrix degradation. Similarly, murine M1 expressed substantial levels of <i>Treml4</i>, as did oxLDL treated macrophages. Transcriptome analysis confirmed that murine <i>Treml4</i> controls the expression of genes related to inflammation and lipid regulation pathways, suggesting a possible role in atherosclerosis. Analysis of <i>Apoe^-/-/Treml4^-/-</i> 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 <i>Treml4</i> represses a specific set of genes related to carbohydrate, ion and amino acid membrane transport. Metabolomic analysis confirmed that <i>Treml4</i> deficiency may promote a beneficial relationship between iron homeostasis and glucose metabolism. Together, our results suggest that <i>Treml4</i> plays a role in the development of cardiovascular disease, as indicated by <i>Treml4</i>-dependent dysregulation of macrophage inflammatory pathways, macrophage metabolism and promotion of vulnerability features in advanced lesions.