TREML4 expression by myeloid cells may play a role in coronary artery disease (HUM1P.308)

Triggering Receptor Expressed on Myeloid cells (TREM) family receptors modulate responses of a variety of leukocytes. We found that TREM-like 4 (TREML4) mRNA is elevated in the peripheral blood of patients with advanced coronary artery calcification (CAC) and that a single nucleotide polymorphism (SNP), rs2803496, tracks with the level of TREML4 mRNA in these patients. In an effort to elucidate the mechanism through which TREML4 in peripheral blood could affect CAC, we began by determining what cells express it. Monocytes and lymphocytes of donors with this SNP expressed very low levels of TREML4 mRNA whereas their neutrophils (PMNs) were strongly positive. Consistent with its association with CAC, we found variation in the levels of TREML4 mRNA in PMNs that correlated rs2803496, and a second SNP rs2803495. Unlike murine Treml4, which has the typical TREM family structure, human TREML4 has a noncanonical leader, lacks a portion of the transmembrane domain (TM) and has no cytoplasmic tail. Characterization of the Treml4 cDNA suggests that this truncated TM domain is sufficient to anchor the protein in the plasma membrane but that the TREML4 native leader sequence is ineffective. Lastly, immunostaining of human atherosclerotic plaques shows TREML4 in macrophage-rich regions, as well as on the endothelium. Together our findings suggest that TREML4 may play an important role in atherosclerosis and CAC but that it is unlikely to function as a typical, DAP12-coupled TREM.