The Role of Apolipoprotein A-I in the Modulation of Cholesterol and Immune Homeostasis

The goal of this work was to examine the role of apoA-I in atherosclerosis and autoimmunity. We used a mouse model lacking the LDL receptor and the apoA-I gene (LDLr-/-,ApoA-I-/- or DKO). LDLr-/- (SKO) mice were used as controls. When fed a cholesterol-containing diet, DKO mice exhibited cholesterol accumulation in the skin and skin-draining lymph nodes (LNs). The LN total cell number was increased, with expansion of T cell, B cell, dendritic cell (DC) and macrophage populations. Interestingly, DKO LN T cells, B cells and DCs had increased cholesterol compared to controls. DKO LN T cells had increased expression of activation markers and proliferation of CD4+CD44high T cells was increased. Plasma autoantibodies were also increased. We concluded that, in the absence of apoA-I, diet-fed DKO mice develop an autoimmune phenotype. These data suggest that apoA-I can modulate immune cell function by regulating cellular cholesterol balance. This, in turn, prevents LN cell expansion, activation and the progression of atherosclerosis. Regulatory T cells (Treg) were increased in LNs of DKO mice. To determine the direct effects of apoA-I on this cell population and the autoimmune phenotype, mice were fed diet for 6 weeks then apoA-I injections began and continued every 48 hours for an additional 6 weeks. After 12 weeks total on diet, apoA-I-treated DKO mice (DKO+A-I) had reduced LN size and reduced LN cell number compared to DKO mice treated with BSA (DKO+BSA). The skin cholesterol was also massively reduced, with inflammatory cell infiltration in the skin reduced compared to DKO+BSA. The LN Treg population was increased even further compared to DKO+BSA. This increase, however, was different than that seen in DKO+BSA mice because it also resulted in a decrease in cellular activation. These data indicate that apoA-I is effective in improving the Treg response in autoimmune mice, preventing autoimmunity. We have identified apoA-I as potential mechanistic link between atherosclerosis and autoimmunity. ApoA-I treatment prevented cholesterol accumulation and improved the Treg response in DKO mice, thus preventing autoimmunity. Therefore, treatment with apoA-I to increase HDL levels may be an important option to consider when devising treatments for both atherosclerosis and autoimmunity.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2010

Author dc:creator

• Wilhelm, Ashley

• Immunology

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10339/14872

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/14872