Inflammation in atherosclerosis

Abstract

Experimental work has elucidated molecular and cellular pathways of inflammation that promote atherosclerosis. Unraveling the roles of cytokines as inflammatory messengers provided a mechanism whereby risk factors for atherosclerosis can alter arterial biology, and produce a systemic milieu that favors atherothrombotic events. The discovery of the immune basis of allograft arteriosclerosis demonstrated that inflammation per se can drive arterial hyperplasia, even in the absence of traditional risk factors. Inflammation regulates aspects of plaque biology that trigger the thrombotic complications of atherosclerosis. Translation of these discoveries to humans has enabled both novel mechanistic insights and practical clinical advances.

Figure 1

This drawing (made with the original MacPaint application by the author) presents an early depiction of the crosstalk between inflammatory cells and intrinsic factor wall cells mediated by cytokines. Work from around the world has now verified the principle points postulated in this primitive picture, a precursor of countless subsequent schemata. The T lymphocyte depicted at the apex of the diagram responds to antigenic stimulation by elaborating cytokines such as interferon gamma (IFN–γ), lymphotoxin (LT), and tumor necrosis factor-alpha (TNF–α). This sequence represents the adaptive immune response. These cytokines impinge upon the macrophage/monocyte depicted in the middle of the diagram that can elaborate mediators of innate immunity such as interleukin-1 and interleukin-6 in response, as well as a material then denoted as platelet-derived growth factor cross-reactive material (PDGFc), and transforming growth factor alpha (TGF–α) Monocytes/macrophages thus comprise a major cell type involved in innate immunity. These cytokines produced by mononuclear phagocytes in turn mediate paracrine signaling to endothelial cells (EC, lower left) or vascular smooth-muscle cells (SMC, lower right). From: Libby P, Salomon RN, Payne DD, Schoen FJ, Pober JS. Functions of vascular wall cells related to development of transplantation-associated coronary arteriosclerosis. Transplant Proc 1989;21(4):3677–3684.

Figure 2

This illustration depicts a sequence of development of allograft arteriopathy proposed in 1991, based on morphologic evaluation of human lesions and in vitro immunologic experiments. A: Circulating T cells and monocytes contact human leukocyte antigen (HLA)-DR– endothelial cells (ECs). HLA-DR– medial smooth-muscle cells (SMCs) reside beneath the internal elastic lamina. B: In early allograft arteriopathy, HLA-DR+ ECs overlie T cells and macrophages within the intima. C: In advanced allograft arteriopathy, SMCs predominate within the deeper layers of the intima. HLA-DR+ ECs, T cells, and macrophages line the lumen. From Salomon RN, Hughes CCW, Schoen FJ, Payne DD, Pober JS, Libby P. Human coronary transplantation-associated arteriosclerosis: evidence for a chronic immune reaction to activated graft endothelial cells. Am J Pathol 1991;138(4):791–798.

Figure 3

The relationship between traditional risk factors for atherosclerosis and inflammation. The concept of inflammation in atherosclerosis in no way diminishes the importance of the traditional risk factors for atherosclerosis depicted at the top of this diagram, including low-density lipoprotein (LDL) and angiotensin II (Ang II). Rather, the concept of inflammatory signaling and the participation of proinflammatory cytokines provides a mechanistic link between traditional risk factors and altered biological responses of the artery wall that drive atherosclerosis and its complications.