Identification of the specific atherogenic and atheroprotective roles of plasmacytoid DCs following in situ inflammatory vs tolerogenic stimulation

Cardiovascular disease (CVD) continues to be the leading cause of death in the developed world, and new strategies for prevention and treatment are desperately needed. Atherosclerosis is an immunologically complex inflammatory condition within the intima of arterial vessel walls and a principal cause of CVD. Initial stages involve the sub-endothelial retention of monocytes that differentiate into foam cells, i.e. lipid-laden macrophages, which are the basis of inflammatory plaques that can rupture and induce ischemic stroke or myocardial infarction. Diverse inflammatory immune cell populations participate in all stages atherosclerosis, of which dendritic cells (DCs) have emerged as a critical regulatory component and a promising target for immunotherapy. Notably, the specific functions of DCs depend on the subpopulation, as some are proatherogenic and others atheroprotective. Plasmacytoid DCs (pDCs) have a particularly dichotomous role, serving as the primary source of proatherogenic type I interferons (INF) while at other times playing key roles in the activation of regulatory T cells (Tregs) that stabilize plaques and prevent rupture. By mimicking the structures, mechanisms of payload delivery, and immunogenicity of viruses, therapeutic formulations can better target DCs and achieve controlled immunomodulation. I therefore hypothesize that pDCs can be biased towards either their atherogenic or atheroprotective roles via controlled stimulation with virus-mimicking nanocarriers. I have previously engineered immunomodulatory nanocarriers (NCs) that target pDCs when mimicking filamentous virions but target a wide range of DC subsets when mimicking spherical virions. The aims of this proposal are consequently to 1) rationally design NCs to target and image DC populations within mouse models of atherosclerosis and 2) use these NCs as immunostimulants to investigate the specific contributions of pDCs towards the maturation of atherosclerotic lesions relative to other DC subsets. Immunotherapies for CVD are only in the early stages of development, and this work will further the understanding of DC-induced inflammation and may reveal novel methods of influencing Tregs during atherosclerosis.