Type 1 diabetes mellitus (T1DM) is associated with cardiovascular complications induced by
atherosclerosis.
Prostaglandin E2 (
PGE2) is often raised in states of
inflammation, including diabetes, and regulates inflammatory processes. In myeloid cells, a key cell type in
atherosclerosis,
PGE2 acts predominately through its
Prostaglandin E Receptor 4 (EP4; Ptger4) to modulate
inflammation. The effect of PGE2-mediated EP4 signaling specifically in myeloid cells on
atherosclerosis in the presence and absence of diabetes is unknown. Because diabetes promotes
atherosclerosis through increased arterial myeloid cell accumulation, we generated a myeloid cell-targeted EP4-deficient mouse model (EP4M-/-) of T1DM-accelerated
atherogenesis to investigate the relationship between myeloid cell EP4, inflammatory phenotypes of myeloid cells, and
atherogenesis. Diabetic mice exhibited elevated plasma
PGE metabolite levels and elevated Ptger4
mRNA in macrophages, as compared with non-diabetic littermates.
PGE2 increased
Il6, Il1b, Il23 and Ccr7
mRNA while reducing Tnfa
mRNA through EP4 in isolated myeloid cells. Consistently, the stimulatory effect of diabetes on peritoneal macrophage
Il6 was mediated by PGE2-EP4, while PGE2-EP4 suppressed the effect of diabetes on Tnfa in these cells. In addition, diabetes exerted effects independent of myeloid cell EP4, including a reduction in macrophage Ccr7 levels and increased early
atherogenesis characterized by relative lesional macrophage accumulation. These studies suggest that this mouse model of T1DM is associated with increased myeloid cell PGE2-EP4 signaling, which is required for the stimulatory effect of diabetes on
IL-6, markedly blunts the effect of diabetes on TNF-α and does not modulate diabetes-accelerated
atherogenesis.