TREML4 (triggering receptor expressed on myeloid cells like 4) is a myeloid-expressed signaling receptor that positively regulates TLR7 signaling in macrophages 1. TREML4 is selectively expressed in pro-inflammatory M1 macrophages, where it dysregulates inflammatory pathways related to leukocyte activation, apoptosis, and extracellular matrix degradation 1. The receptor is particularly enriched in intermediate monocytes (Ly6C+Treml4+ in mice) 2. In cardiovascular disease, TREML4 expression positively correlates with coronary artery calcification and is localized within macrophages surrounding necrotic cores of calcified plaques 3. TREML4 dysregulation promotes atherosclerosis progression through inflammatory pathway activation and altered macrophage metabolism, with Treml4-knockout mice showing reduced atherosclerotic plaque burden and lesion complexity 1. TREML4 expression in blood leukocytes associates with severe coronary lesion extent and is influenced by genetic polymorphisms (rs2803495 and rs2803496) 45. In sepsis, TREML4 controls both the initial inflammatory cytokine storm and subsequent immune suppression phases, emerging as a potential therapeutic target when conventional TLR4-based approaches have failed clinically 67. Overall, TREML4 functions as a pro-inflammatory regulator in macrophages with significant implications for atherosclerosis and sepsis pathogenesis.