Oxidized Lipid Species Promote Atherogenic Phenotypes in Innate and Adaptive Immune Cells

Abstract

Atherosclerosis is an immune mediated hyperinflammatory disease driven by the retention and oxidation of low-density lipoprotein (LDL) in the vessel wall. The goal of this work was to determine how oxidized LDL (oxLDL) reshapes the phenotype and function of innate and adaptive cells. Chapter 2 addresses the gap in knowledge regarding what causes regulatory T cell (Treg) dysfunction in atherosclerosis, and shows that oxidized phospholipids within oxLDL, namely oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (oxPAPC), alters Treg differentiation and inhibits their atheroprotective function. This oxPAPC-driven effect is partially IFN- signaling dependent, prompting an investigation of the role of Treg IFN- receptor (IFNR) signaling in a bone marrow transplant mouse model of atherosclerosis in Chapter 3. Treg IFNR deficiency alters atherosclerosis severity in mice but does so in a sex-dependent manner, with deficiency increasing disease burden in females and reducing it in males. This builds on previous work that has shown sex-dependent outcomes for IFN- inhibition in atherosclerosis mouse models, and adds nuance to the described proinflammatory function of IFN-. Chapter 4 demonstrates oxLDL immune complexes, which are increased in the circulation of atherosclerosis and autoimmune patients, trigger long-term changes in DCs that are distinct from alterations caused by oxLDL alone, better characterizing how this prevalent atherosclerotic antigen might contribute to chronic inflammation. The summary of these chapters and potential future directions of this work is the focus of Chapter 5. Ultimately, these studies add to our understanding of how oxidized lipids in atherosclerosis modulate the immune responses that are critical to driving and resolving disease.