Circulation Topic Review Immune Modulation of Atherosclerosis

The notion that inflammation plays a role in atherosclerosis dates to separate observations by Virchow and von Rokitansky in the middle of the 19 century that atherosclerotic blood vessels contained evidence of cellular inflammation. This concept remained stagnant until the 1970s, when Russell Ross demonstrated that monocyte adhesion to the endothelial surface was an early and essential feature of atherosclerosis.1 These observations, coupled with knowledge that modified low-density lipoprotein (LDL) supports foam cell formation and promotes atherosclerosis disease activity,2 focused early investigative efforts on monocytes and macrophages, the foam cell precursors. Indeed, it is clear that neutrophils3 and monocytes enter lesion-prone arterial sites, the latter differentiate into macrophages, and then take up accumulated LDL-cholesterol to form foam cells and early atherosclerotic lesions. Innate immune responses, such as recognition of modified LDL-derived epitopes via macrophage Toll-like receptors, prompts cytokine-mediated recruitment of other inflammatory cells to the lesion4 that, in turn, promote the adaptive immune responses responsible for the chronic inflammation of atherosclerosis. Emerging evidence has helped to refine this paradigm and identify critical events in adaptive immunity that could represent therapeutic opportunities for immune modulation of atherosclerosis. Activated endothelium is characterized by adhesion molecule expression and reduced barrier function that mediate the recruitment of both monocytes5 and T-cells into lesion-prone sites in the arterial wall. With regard to T-cells, histological examination of atherosclerotic lesions demonstrate the presence of both CD4 T helper (Th) cells, CD8 cytotoxic T (Tc) cells, and regulatory T cells (Treg) in lesions, although Th cells generally predominate. Lesional T-cells represent a cellular minority (compared to monocytoid cells), but are known to profoundly impact atherosclerosis with Th cells generally promoting the disease and Tregs exhibiting inhibition. Reconstitution of CD4 Th cells into Scid mice accelerates atherosclerosis6 as does expansion of lesional Th cell numbers due to limiting Treg activity.7 With regard to Tregs, their population in the arterial wall is enhanced by CXCL10 deficiency, leading to reduced atherosclerosis.8 In this regard, it is interesting to note that diet-induced hypercholesterolemia profoundly limits the population and function of Treg cells in atherosclerotic lesions.9 Reversal of hypercholesterolemia, however, prevents the loss of lesional Tregs and preserves their function. These data suggest that cholesterol lowering may impact atherosclerosis, at least in part, by changing the distribution and activity of T-cell populations within the arterial wall. The profound impact of T-cells on atherosclerosis fits with their known function(s) in immune modulation. Histology of atherosclerotic lesions often demonstrate colocalization of T-cells, with antigen presenting cells such as dendritic cells and MHC class II expressing macrophages. These findings fit with models of adaptive immunity whereby T-cells become activated through interaction with antigen presenting cells. The latter are typically mature dendritic cells that have a high surface density of MHC-antigen complexes that are required for conversion of naïve T-cells to effector/memory cells that propagate adaptive immunity. Thus, relatively few Th cells and dendritic cells have the capacity to promote expansion of adaptive immunity. Classical models for the transition from innate (immediate) to adaptive (long-term) immunity involves migration of T-cells and mature dendritic cells to secondary lymphoid organs, where dendritic cell antigen presentation affords T-cell differentiation and activation. One key component of this process is the chemokine receptor type 7 (CCR7) that is required for lymphoid organ colocalization and the interaction of dendritic and T-cells. Accordingly, deficiency of CCR7 results in defects in the transition from innate to adaptive immune responses, and this paradigm extends to atherosclerosis. Mice lacking CCR7 exhibiting a 50% reduction in lesion formation on the LDL receptor-null background,10 with no impact on cholesterol levels by CCR7 status. In lesions, the lack of CCR7 was associated with reduced macrophage content and, surprisingly, increased numbers of dendritic cells and T-cells.10 These latter 2 cell types were notably absent from lymph nodes of CCR7-null mice, suggesting that atherosclerosis is dependent on cycling of T-cells and dendritic cells between the vessel wall and secondary lymphoid organs. These observations indicate that our focus on the arterial wall as the major site of atherosclerosis-associated inflammation needs to be revisited to include secondary lymphoid organs. Moreover, the possibility exits that manipulation of lymphoid tissue could represent an attractive and accessible target for therapeutic intervention of atherosclerosis. Dendritic cells (as well as classes of B-cells and macrophages) promote inflammation primarily through antigen presentation, a process that involves endocytosis of extracellular antigens followed by their loading onto MHC class II molecules in late endosomes and subsequent cell surface expression of the stable MHC class II antigen complexes. MHC class II maturation depends on CD74, and mice lacking this so-called invariant chain have defective antigen presenFrom the Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01655. Correspondence to John F. Keaney, Jr, MD, Division of Cardiovascular Medicine, UMass Medical School, 55 Lake Avenue North, Worcester, MA, 01655. E-mail [email protected] (Circulation. 2011;124:e559-e560.) © 2011 American Heart Association, Inc.