Inflammation, Immunity, and Infection in Atherothrombosis: JACC Review Topic of the Week

Abstract

Observations on human and experimental atherosclerosis, biomarker studies, and now a large-scale clinical trial support the operation of immune and inflammatory pathways in this disease. The factors that incite innate and adaptive immune responses implicated in atherogenesis and in lesion complication include traditional risk factors such as protein and lipid components of native and modified low-density lipoprotein, angiotensin II, smoking, visceral adipose tissue, and dysmetabolism. Infectious processes and products of the endogenous microbiome might also modulate atherosclerosis and its complications either directly, or indirectly by eliciting local and systemic responses that potentiate disease expression. Trials with antibiotics have not reduced recurrent cardiovascular events, nor have vaccination strategies yet achieved clinical translation. However, anti-inflammatory interventions such as anticytokine therapy and colchicine have begun to show efficacy in this regard. Thus, inflammatory and immune mechanisms can link traditional and emerging risk factors to atherosclerosis, and offer novel avenues for therapeutic intervention.

Keywords: basic & translational research.

Central Illustration:. Acute and chronic and direct and indirect effects of infection can augment cardiovascular risk.

The left side of this diagram depicts the effects of infections, generally acute, on aggravating myocardial ischemia as detailed in Figure 3, and on producing vascular dysfunction in systemic and coronary arteries that can favor the development of cardiovascular events. The right side of the figure portrays how direct infection or echoes in the arterial wall of systemic or remote inflammation as depicted in detail in Figures 1 and 2 can accelerate atherosclerosis. Both acute and chronic infections can heighten thrombotic risk by inducing a procoagulant state, for example increasing tissue factor procoagulant production and fibrinogen elaboration by the hepatocyte as shown in Figure 2 and impairing fibrinolysis by augmenting the expression of PAI-1 as part of the acute phase response. Thus, both acute and chronic infections can influence cardiovascular risk and infections remote from the artery or with potentially within the artery and can thereby lead to augmented risk of cardiovascular events.

Figure 1.. Infection and immunity in atherogenesis.

The central triangle represents the key cell types of the atheroma: endothelium, smooth muscle, and macrophage foam cells representative of the leukocytes found in plaques. These cells found within the atherosclerotic plaque can produce cytokines, notably interleukin-1 (IL-1), that can contribute to a positive feedback loop as IL-1 can induce its own gene expression in the source cell, an autocrine pathway, or activate neighboring cells through juxtacrine or paracrine pathways. Systemic mediators or these locally produced cytokines can elicit further mediator release from cells in the atheroma producing local echoes of systemic inflammation. The surrounding semicircle of cells represents the lymphocytes that interact with cells within the atheroma and some key mediators by which they can modulate the local inflammatory and immune response within the plaque. Regulatory T cells (Treg) elaborate transforming growth factor beta (TGF-b), a mediator that exerts anti-inflammatory and pro-fibrotic actions on many cell types. The Th2 lymphocytes can mute inflammatory responses and promote resolution or healing responses through the elaboration of interleukin-10 and interleukin-4. Th1 lymphocytes can release interferon gamma (IFN-g) that can potently produce pro-atherogenic functions of the three major cell types depicted in the arterial plaque. The induction of class II major histocompatibility molecules on the surface of antigen-presenting cells in the plaque such as the macrophage can in turn enhance their ability to stimulate the afferent limb of the adaptive immune response. Th17 cells elaborate IL-17, which has mixed effects on atheromata, perhaps promoting inflammation but also augmenting fibrosis. B lymphocytes can also modulate atherosclerosis. B1 cells (not depicted here) can secrete natural IgM antibodies that appear atheroprotective. Many such natural antibodies recognize epitopes associated with modified lipoproteins. B2 cells can elaborate cytokines and IgG antibody that can stimulate atherogenesis, based on observations in mice. CD8 lymphocytes can kill virally infected cells including those in the atheroma releasing DAMPs that can augment inflammatory activation of many cells types through engagement of TLRs. Microorganisms themselves, as depicted by the bacillus in the diagram, can provide PAMPs such as lipopolysaccharide or peptidoglycans that activate cells in the atherosclerotic plaque through engagement of TLRs. This complex network involves interactions between innate immune pathways and both humoral and cellular adaptive immunity.

Figure 2.. Chronic infections can accelerate atherogenesis and set the stage for thrombotic complications directly and indirectly.

The left side of this diagram lists a number of examples of chronic infections or collections of microorganisms that can produce indirect effects on the cardiovascular system. For example, chronic infections can release cytokines, activate leukocytes, and elaborate pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides or peptidoglycan components of bacterial cell walls. Tissue injury can produce and provoke the release of damage-associated molecular patterns (DAMPs). Cytokines, through their cognate receptors, and PAMPs and DAMPs often through toll-like receptors (TLRs), can contribute to the activations of cells involved in atherogenesis including the intrinsic inhabitants of the normal artery wall, the endothelial and smooth muscle cells, or the leukocytes that accumulate in atherosclerotic lesions such as the macrophage foam cell. Activated white blood cells can also elaborate inflammatory mediators including cytokines, lipid mediators, and reactive oxygen species that may enhance atherogenic functions of cells within the atheroma. Cytokines through the intermediary of interleukin-6 can elicit the acute phase response from hepatocytes. Among the acute phase reactants elaborated by hepatocytes during this response, fibrinogen can increase coagulability and plasminogen activator inhibitor-1 (PAI-1) can impair fibrinolysis. These changes in the fluid phase of blood can hasten the formation of thrombi and impair their resolution by inhibiting fibrinolysis. The right side of the diagram indicates various viral and microbial pathogens which studies have implicated in atherogenesis. The infection of endothelial and smooth muscle cell and of lesion-associated leukocytes can directly promote inflammation within the plaque.

Figure 3.. Acute infections can aggravate myocardial oxygen/supply imbalance.

The innate immune response to many infections involves the release of endogenous pyrogens, principally interleukin-1, that affect thermoregulatory centers in the central nervous system and elicit fever. The increased metabolic demands can augment oxygen requirements of the myocardium. The tachycardia that usually accompanies fever also causes a chronotropic increase in myocardial oxygen demand. Thus, in acute infections, both increased metabolic demand and a hyperkinetic state of the circulatory system conspire to augment oxygen requirements of the myocardium as well as of peripheral tissues. In patients with sepsis, hypotension can limit the diastolic perfusion of the coronary arteries leading to a reduction in myocardial oxygen supply. Pneumonitis or adult respiratory distress syndrome, or systemic inflammatory response syndrome (SIRS) can lead to hypoxemia, further reducing myocardial oxygen delivery. Thus, the acute response to infection can lead to an imbalance between myocardial oxygen supply. Particularly in the case of preexisting coronary artery disease, this imbalance between oxygen supply and demand can lead to a type 2 myocardial infarction, depicted by the cyanosis over the left ventricle in this diagram.