Abstract 653: Endothelial ASC Modulates Early Atherosclerosis by Limiting Monocyte Recruitment
The inflammasome consists of an innate immune receptor, the adaptor molecule ASC, and the effector Caspase-1 that is responsible for processing signature cytokines such as IL-1beta. The exact role of the inflammasome in atherosclerosis is not clear since both pathogenic and dispensable roles have been reported. Notably, ASC has functions that may impact atherosclerosis but are unrelated to the inflammasome, for example the induction of apoptosis and the regulation of pro-inflammatory transcription factors. The various roles of ASC (i.e. IL-1beta processing, cell death, NF-kappaB and AP-1 regulation) may modulate the progression of atherosclerosis depending on lesion stage and explain the divergent findings highlighted above.
To examine the role of ASC in lesion progression, we bred ASC-deficient mice onto the Ldlr-/- background and initiated a cholesterol-rich diet (CRD). In the early stages of atherogenesis (2 weeks of CRD), ASC-/-Ldlr-/- mice had a significantly increased lesion surface area, leukocyte content, and rate of Ly6Chi monocyte recruitment in the ascending aorta. Bone marrow transplant experiments suggested that ASC deficiency in the vessel wall was responsible for this phenotype. Knockdown of ASC by siRNA in cultured human umbilical vein endothelial cells lead to increased TNF-alpha-induced expression of VCAM1 and monocyte adhesion in parallel-plate flow chamber assays. Monocyte adhesion was not affected by silencing Caspase-1, suggesting that the effect of ASC was independent of the inflammasome. Preliminary findings implicate MAPK family members in ASC-mediated regulation of endothelial adhesion molecules.
At 16 weeks of a CRD ASC-/-Ldlr-/- mice had a significantly decreased lesion size compared with controls. Lesions from ASC-/-Ldlr-/- mice had a smaller necrotic core area accompanied by decreased numbers of apoptotic leukocytes as determined by active Caspase-3 and TUNEL positivity. These data are in accordance with the pro-atherogenic role of ASC in later stages of atherosclerosis. However our findings demonstrate a novel protective role for ASC in the early stage, which represents a non-inflammasome function via modulation of endothelial-associated adhesion molecules.
Author Disclosures: A.C. Lau: None. S.J. Hyduk: None. J. Jongstra-Bilen: None. M.I. Cybulsky: None.
- © 2014 by American Heart Association, Inc.