Beyond vascular inflammation--recent advances in understanding atherosclerosis

Abstract

Atherosclerosis is the most life-threatening pathology worldwide. Its major clinical complications, stroke, myocardial infarction, and heart failure, are on the rise in many regions of the world--despite considerable progress in understanding cause, progression, and consequences of atherosclerosis. Originally perceived as a lipid-storage disease of the arterial wall (Die cellularpathologie in ihrer begründung auf physiologische und pathologische gewebelehre. August Hirschwald Verlag Berlin, [1871]), atherosclerosis was recognized as a chronic inflammatory disease in 1986 (New Engl J Med 314:488-500, 1986). The presence of lymphocytes in atherosclerotic lesions suggested autoimmune processes in the vessel wall (Clin Exp Immunol 64:261-268, 1986). Since the advent of suitable mouse models of atherosclerosis (Science 258:468-471, 1992; Cell 71:343-353, 1992; J Clin Invest 92:883-893, 1993) and the development of flow cytometry to define the cellular infiltrate in atherosclerotic lesions (J Exp Med 203:1273-1282, 2006), the origin, lineage, phenotype, and function of distinct inflammatory cells that trigger or inhibit the inflammatory response in the atherosclerotic plaque have been studied. Multiphoton microscopy recently enabled direct visualization of antigen-specific interactions between T cells and antigen-presenting cells in the vessel wall (J Clin Invest 122:3114-3126, 2012). Vascular immunology is now emerging as a new field, providing evidence for protective as well as damaging autoimmune responses (Int Immunol 25:615-622, 2013). Manipulating inflammation and autoimmunity both hold promise for new therapeutic strategies in cardiovascular disease. Ongoing work (J Clin Invest 123:27-36, 2013; Front Immunol 2013; Semin Immunol 31:95-101, 2009) suggests that it may be possible to develop antigen-specific immunomodulatory prevention and therapy-a vaccine against atherosclerosis.

Keywords: Atherosclerosis; Autoimmunity; Macrophage; Monocyte; T cell; Vaccine.

Fig. 1

Proposed origin and fate of myeloid cells in the atherosclerotic plaque in mice. Early plaque macrophages originate from inflammatory Ly6C^high monocytes that transmigrate into the plaque and differentiate (1). A second monocyte subset, patrolling Ly6C^low monocyte is thought to patrol the vessel wall to remove debris and dead endothelial cells. However, Ly6C^low monocyte may also contribute to the pool of plaque macrophages by transmigration and differentiation into macrophages. Ly6C^low monocytes in the plaque may also originate by conversion from Ly6C^high monocytes to give rise to macrophages (2). Alternatively, it has also been speculated whether plaque macrophages may stem from migrated adventitial macrophages that are possibly derived from the primitive yolk sac during embryogenesis and that may have the potential to self-renew. Depending on the context, macrophages may ingest lipids and turn into foam cells (3) or die (4). It has recently been reported that the pool of plaque macrophages can independently be maintained in the later stages of disease by direct proliferation in situ (5). Besides their differentiation into macrophages, Ly6C^high monocytes may transmigrate into the plaque, engulf, and present antigens by MHC-II, before leaving the plaque and migrating into peripheral lymph nodes (6). Likewise, dendritic cells (not shown) and macrophages can migrate into the lymphatic system to present antigens to T cells and initiate an immune response

Fig. 2

Hypothesized mechanisms of T cell-dependent autoimmunity in mice. Generation of T cell clones and antibodies that recognize self-peptides from ApoB-100, the protein moiety of low-density lipoprotein (LDL), have been proposed as main pathways of T cell-dependent autoimmunity. Antigen-specific, pro-atherogenic T cells are primed in peripheral lymph nodes (lower schematic), but remain incompletely differentiated after first presentation of self-peptides by dendritic cells or Ly6C⁺ monocytes migrating from the plaque. (1) A primed T cell may leave the lymph node and home to the plaque to allow for terminal differentiation: In the plaque, presentation by IL-12⁺ APCs to primed T cells is thought to elicit a pro-atherogenic T_H1 type immune response with the lead cytokines TNF-α and IFN-γ. Conversely, presentation by Flt3⁺ tolerogenic dendritic cells can induce an atheroprotective response with conversion of the primed T cell into T_reg cells and secretion of the anti-inflammatory mediators IL-10 and TGF-β (upper schematic). (2) Alternatively, a primed T cell can differentiate into a follicular-helper T cells (T_FH), which induces generation and secretion of ApoB-100-specific IgG antibodies by plasma cells in the lymph node or tertiary lymphoid organs (lower schematic)