Inflammation and its resolution as determinants of acute coronary syndromes

Abstract

Inflammation contributes to many of the characteristics of plaques implicated in the pathogenesis of acute coronary syndromes. Moreover, inflammatory pathways not only regulate the properties of plaques that precipitate acute coronary syndromes but also modulate the clinical consequences of the thrombotic complications of atherosclerosis. This synthesis will provide an update on the fundamental mechanisms of inflammatory responses that govern acute coronary syndromes and also highlight the ongoing balance between proinflammatory mechanisms and endogenous pathways that can promote the resolution of inflammation. An appreciation of the countervailing mechanisms that modulate inflammation in relation to acute coronary syndromes enriches our fundamental understanding of the pathophysiology of this important manifestation of atherosclerosis. In addition, these insights provide glimpses into potential novel therapeutic interventions to forestall this ultimate complication of the disease.

Keywords: apoptosis; inflammation; inflammation resolution; macrophage; myocardial infarction; plaque necrosis.

Figure 1. Inflammation in plaque rupture and thrombosis

This diagram shows a cross section the intima of part of an artery affected by atherosclerosis. Altered hydrodynamics, illustrated in the upper left, cause loss atheroprotective functions of endothelial cells — including vasodilator, anti-inflammatory, pro-fibrinolytic, and anti-coagulant properties. Antigens presented on antigen-presenting cells such as dendritic cells (DCs) can activate Th1 lymphocytes to produce interferon gamma (IFN-γ), which activates macrophages (MΦ, yellow). Other subtypes of lymphocytes (shown in blue) include Th2 lymphocytes, which can elaborate the anti-inflammatory cytokine interleukin 10 (IL-10) and regulatory T cells that secrete the anti-inflammatory cytokine transforming growth factor beta (TFG-β). On its surface, the macrophage contains Toll-like receptors (TLRs) 2 and 4, which can bind PAMPs and DAMPs (see text). The intracellular TLRs 3, 7, and 9 may also contribute to lipid accumulation and other pro-atherogenic functions of the macrophage. Macrophages can undergo stress of the endoplasmic reticulum (ER) under atherogenic conditions. Cholesterol crystals found in plaques can activate the NLRP3 inflammasome (see text) that can generate mature IL-1β from its inactive precursor. The activated macrophage secretes collagenases that can degrade the triple helical interstitial collagen that lends strength to the plaque's fibrous cap. Activated macrophages also express tissue factor, a potent pro-coagulant, and elaborate pro-inflammatory cytokines that amplify and sustain the inflammatory process in the plaque. When the plaque ruptures due to a collagen-poor, weakened fibrous cap, blood in the lumen can contact tissue factor in the lipid core, triggering thrombus formation (red). When the thrombus forms, polymorphonuclear leukocytes (PMNs) can accumulate and elaborate myeloperoxidase (MPO), which in turn elaborates the potent pro-oxidant hypochlorous acid. Dying PMNs extrude DNA that can form neutrophil extracellular traps (NETs), which can entrap leukocytes and promote thrombosis. Other inflammatory cells modulate atherosclerosis. B2 lymphocytes secrete natural antibody that can inhibit plaque inflammation. On the other hand, B1 lymphocytes, in part via B-cell activating factor (BAFF), can promote inflammation and plaque complication. Mast cells can augment atherogenesis by releasing histamine and the cytokines IFN-γ and IL-6. The consequences of a given plaque rupture depend not only on the solid state of the intimal plaque, but also on the fluid phase of blood, as depicted in the upper right. Systemic inflammation can give rise to cytokines, culminating in the overproduction of IL-6, the trigger of the hepatic acute phase response. The acute phase reactant fibrinogen participates directly in thrombus formation. Another acute phase reactant, plasminogen activator inhibitor-1 (PAI-1), can impair fibrinolysis by inhibiting the endogenous fibrinolytic mediators, urokinase and tissue-type plasminogen activators (uPA and tPA).

Figure 2. Life, death, and transit of macrophages in generating the plaque's “necrotic” core

Blood monocytes interact with adhesion molecules expressed by endothelial cells exposed to inflammatory mediators. They first roll and attach more firmly, and ultimately diapedese into the intima in response to chemoattractant molecules that bind to surface receptors on the leukocyte — exemplified here by chemokine receptor 2 (CCR2). The monocytes recruited to the intimal lesion can proliferate, giving rise to daughter cells, or can differentiate into macrophages with a pro-inflammatory slant (denoted M1) or those that are alternatively activated (denoted M2). Macrophages can traffic, including leaving the plaque by emigration, as shown here on the macrovascular surface. Retention factors such as netrin-1 or semaphorin-3 can promote retention accumulation of mononuclear phagocytes in the plaque. Macrophages can die by oncosis (sometimes called necrosis) or by programmed cell death (apoptosis). Advanced plaques show a defect in clearance of apoptotic cells leading to their accumulation, a process denoted “mummification” due to a defect in efferocytosis (see text). Dying cells can also release apoptotic bodies and microparticles bearing the potent pro-coagulant tissue factor that triggers thrombus formation in disrupted plaques. The detritus of dead and dying cells that accumulate due to defective efferocytosis give rise to the lipid-rich “necrotic” core of the plaque.