Abstract 1210: Interferon-gamma-induced CD40/CD40 Ligand Pathway Activation Mediates Atherosclerotic Plaque Progression and Destabilization in ApoE-Knockout Mice

Abstract

Background: A triggering role of interferon-gamma (IFN-g) is suggested in atherosclerotic plaque formation by activating inflammatory process. Soluble mutant of IFN-g receptor (sIFNgR) blocks IFN-g-induced activation of the target cells in vivo. The immune mediator CD40 ligand (CD40L) and its receptor CD40 are crucial for initiation of plaque formation and for progression and destabilization of advanced plaque by producing monocyte chemoattracting protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9). We assessed the hypothesis that postnatal inhibition of intrinsic IFN-g would reduce and stabilize advanced plaques via inhibition of the CD40L/CD40 pathway. Methods and Results: From 8-week old (w), apoE-knockout (apoEKO) mice were fed daily high-fat diet. At 12 w when aortic plaques had been established, mice were randomized to 2 groups: sIFNgR-treated mice received gene transfer of naked DNA plasmid encoding sIFNγR into the thigh muscle twice at 12 and 14 w. Mock-treated mice received the empty plasmid. At 16 w, mock-treated apoEKO mice showed progression of aortic plaque. They had massive oil red O-stained lipid core and bulky MOMA2-labeled macrophage accumulation accompanied by thin Azan-stained fibrous cap with little smooth muscle cells (SMCs). These findings demonstrated markedly low plaque stability. sIFNgR treatment reduced plaque area by more than 50% versus mock-treated mice. Moreover, sIFNgR treatment stabilized the plaque by decreasing lipid and macrophage areas and increasing the areas of SMCs and collagen. In mock-treated mice, CD40 and CD40L as well as MCP-1 and MMP-9 were markedly upregulated in aortic plaque at 16 w, which were inhibited by sIFNgR treatment. sIFNgR treatment not only reduced the mobilization of peritoneal macrophages but also attenuated the CD40L/CD40 expressions of macrophages. Circulating monocyte count and serum cholesterol levels were not affected by sIFNgR treatment. Conclusions: It was suggested that intrinsic IFN-g function blocking reduced and stabilized advanced plaque in apoEKO mice in part by inhibiting CD40L/CD40 pathway. Targeting IFN-g may be a new strategy for regression and stabilization of atherosclerosis.