Defining a Role for DPP4 in Inflammation and Atherosclerosis

Atherosclerosis is an accumulation of lipid-rich plaques within arteries and a leading cause of death worldwide. Chronic low-grade inflammation is characteristic of atherosclerosis, where monocytes and macrophages play a critical role in the progression or regression of plaque. Dipeptidyl peptidase 4 (DPP4) is increased in conditions of metabolic dysfunction, and there is a strong association between monocyte DPP4 and the development of atherosclerosis. However, a causal mechanism linking increased monocyte DPP4 activity and atherogenesis remains to be revealed. We hypothesize that DPP4 regulates proteins in circulation and in macrophages to drive inflammation and atherosclerosis progression. Using in vivo and in vitro inflammatory models, we identified that DPP4 activity is increased during inflammation, and Dpp4 mRNA is upregulated in pro-inflammatory polarized macrophages. We also found that mononuclear phagocyte DPP4 may have a role in regulating circulating immune cell populations. Ependymin-related 1 (EPDR1) was identified as a DPP4 substrate via N-terminal enrichment mass spectrometry, where transcript expression was decreased in pro-inflammatory and anti-inflammatory polarized BMDMs from males. Additionally, we found correlations between circulating DPP4 protein and Hba1c and LDLc, while both DPP4 activity and protein correlated with HDLc in patients. EPDR1 increased with age and correlated with LDLc and plasma triglycerides in apoe⁻ᐟ⁻ mice, while EPDR1 decreased with age in patients. These data suggest a role of DPP4 and EPDR1 in inflammation, macrophage phenotype, and metabolic dysfunction.