Inflammation in Atherosclerosis

The innate or natural immune response is the body’s rapid first line of defense for environmental threats (eg, trauma and infection), responding long before an immune defense is mounted.1,2 This response involves a series of reactions that have evolved to limit damage, isolate pathogens (noxious agents), and initiate repair processes. Cells distinguish between pathogen and self by using signals from pattern-recognition receptors, scavenger receptors (CD-36, SR-A), and Toll-like receptors (TLRs) on macrophage and dendritic cells.2 These receptors recognize pathogen-associated patterns in nucleic acids, proteins, carbohydrates, and lipids. Flow-dependent regulation of TLR2 surface expression in endothelial cells and ligation of TLR1, TLR2, and TLR4 in plaque result in recruitment of adaptor protein myeloid differentiation factor 88, followed by activation of nuclear factor-κB and mitogen-activated protein kinases.1–4 This results in a cascade of proinflammatory molecules such as interleukin (IL)-6 that drive C-reactive protein (CRP) production, chemokines that act as chemoattractants, and serine proteases that drive thrombosis, all of which contribute to inflammation and pathogen clearance.Accumulating evidence supports a central role for inflammation in preclinical atherosclerosis, with acute coronary syndrome (ACS) as a principle clinical expression.4 Indeed, ACS, ischemic brain syndrome (stroke/transient ischemic attack), and peripheral arterial occlusion1–4 result from a chronic inflammatory process, as well as disorders of lipid metabolism, modified by genetic and environmental factors. Arterial wall function and structure are modulated by interactions between injurious agents, blood vessel wall elements and monocytes, T lymphocytes, and platelets. Invading mononuclear cells release enzymes (eg, matrix metalloproteinases [MMPs]) that degrade collagen and elastin, thereby allowing cells to invade by disrupting matrix layers that otherwise stabilize developing plaque (Figures 1 and 2⇓). Clot forming and inflammatory pathways then work in tandem to accelerate local macrophage and T-cell activation, which contributes to plaque erosion or rupture, forming a …