TREML4 affects lesion composition but not calcification in the Apolipoprotein E deficient model of experimental Atherosclerosis

Abstract

The Triggering Receptor Expressed on Myeloid cells-like 4 (Treml4) is a member of the TREM receptor family which are recognized fine-tuners of the inflammatory response. We have previously found that Treml4 expression correlates to increased risk of Human Coronary Arterial Calcification and Acute Coronary Syndrome. Moreover, we show that carriage of either one of the eQTL SNPs previously identified to permit Treml4 expression, confers the highest treml4 expression in human inflammatory macrophages when compared to alternative activated macrophages. However, the exact role of Treml4 in the pathogenesis of coronary diseases remains incompletely defined. To elucidate the role of Treml4 in atherosclerosis, we investigated whether treml4 deficiency affected pathogenesis in the Apolipoprotein E knockout mouse (apoe^−/−). We found that aortas from apoe^−/− mice had increased treml4 expression when compared to wild type and that treatment with either LDL or oxLDL upregulated macrophage treml4 expression in vitro. After a western diet, overall plaque burden and calcification in the aortic sinus of apoe^−/−/treml4^−/− mice remained unchanged compared to controls. However, we found that treml4 deficiency resulted in less complex lesions as indicated by decreased foam cell content, plaque necrosis and collagen deposition as well as dysregulation of matrix metalloproteinases expression within the plaques. Moreover, less collagenous metaplasia was observed in the brachiocephalic artery of apoe^−/−/treml4^−/− mice. Taken together, our results suggest that Treml4 contributes to the inflammatory mechanisms and extracellular matrix regulation associated with lesion complexity without affecting lesion burden or calcification.