Abstract 50: Regulation of Peripheral Tissue Inflammation Links Autoimmunity and Atherosclerosis
Previous publications from our laboratory show that cholesterol-fed LDLr-/-, apoA-I-/- (DKO) mice develop accelerated atherosclerosis, as well as, a severe autoimmune disorder not seen in diet-fed LDLr-/- mice (SKO). This phenotype is characterized by the expansion of cholesterol loaded T cells within lymphoid organs such as skin draining lymph nodes and spleen as well as the manifestation of aberrant T cell responses. In order to examine the link between the progression of atherosclerosis and the onset of autoimmunity we examined the type and amount of immune cell infiltration in both the aorta and the skin of DKO and SKO mice fed an atherogenic diet for 12 weeks. In a subset of mice the immunomodulator, Fingolimod (FTY720), a sphingosine analogue was administered along with the diet. After 12 weeks, plaque burden in the aortic root was measured as both neutral lipid accumulation, and as the type and number of immune cells present. As expected, diet alone increased both lipid and immune cell infiltration in the aortic root, as well as in the skin of DKO compared to SKO mice. Interestingly, FTY-diet DKO mice showed a sharp reduction in both lipid accumulation as well as CD4+ cell infiltration in the aortic root. This decrease in aortic lipid deposition in FTY-diet DKO was well below that of any of the other groups, including diet-only SKO mice, while FTY-diet SKO were not different than diet-only SKO mice. These data suggest that heightened aortic inflammation observed in response to dietary cholesterol in the absence of apoA-I, renders the DKO aorta more susceptible to the immunomodulatory effects of FTY. Quite unexpectedly, the skin of FTY-diet DKO mice continued to show massive cholesterol accumulation and inflammation with a preservation of subcutaneous fat, in light of the dramatic reduction in aortic infiltrates observed. When DKO mice lacking T and B cells (Rag1-/-, LDLr-/-, apoA-I-/-) were studied, massive skin cholesterol accumulation was still observed and TKO mouse dermis showed infiltrates largely composed of neutrophils and monocytes, suggesting that dermal cholesterol imbalance, in the absence of apoA-I, was the basis for disease initiation in the skin. Overall, these studies illustrate the vastly different roles of apoA-I and immunomodulatory drugs in skin versus aorta cholesterol balance.
- © 2012 by American Heart Association, Inc.