Macrophage death and defective inflammation resolution in atherosclerosis

Key Points

  • Atherothrombotic vascular disease (ATVD) is the leading cause of death in the industrialized world, and this problem is growing owing to the increase in obesity and insulin resistance worldwide. ATVD develops as a macrophage-dominant maladaptive inflammatory response to subendothelial lipoproteins.

  • A fundamental aspect of this maladaptive inflammatory response is a failure to resolve inflammation, which normally involves the suppression of inflammatory cell influx, effective phagocytic clearance of apoptotic cells and promotion of inflammatory cell egress. The mechanism of failed inflammation resolution in atherosclerosis is not known, but it is likely to involve defective generation or action of anti-inflammatory cytokines (for example, interleukin-10), pro-resolution lipid mediators (for example, lipoxins) and transcription factors (for example, the liver X receptor family) that normally carry out this process.

  • In advanced atherosclerosis, there is continual recruitment of inflammatory monocytes, and the macrophages that differentiate from these monocytes in lesions may favour the classically activated (M1) subtype, which promote inflammation, over the alternatively activated (M2) subtype, which participate in inflammation resolution. Egress of inflammatory macrophages in advanced atherosclerotic lesions is also defective.

  • Macrophage apoptosis coupled with defective clearance of these apoptotic cells (efferocytosis) in advanced atherosclerotic lesions is a particularly important process because it leads to the generation of plaque necrosis, which is a key feature of the types of atherosclerotic lesions that cause ATVD. One key mechanism of macrophage apoptosis in this setting is a pathway in which the endoplasmic reticulum stress pathway known as the unfolded protein response, perhaps in combination with pattern recognition receptor activation, triggers Ca2+-dependent apoptosis.

  • The mechanisms of defective efferocytosis in advanced atheroma are not known, but may involve deficiency, dysfunction and/or competitive inhibition of receptors, ligands and other factors involved in apoptotic cell recognition and engulfment.

  • The ability to translate the complex process of plaque progression into an integrated molecular and cellular concept of defective inflammation resolution provides a useful way to understand how atherosclerosis leads to clinical disease and how plaque progression may be prevented by new therapeutic approaches.

Abstract

A key event in atherosclerosis is a maladaptive inflammatory response to subendothelial lipoproteins. A crucial aspect of this response is a failure to resolve inflammation, which normally involves the suppression of inflammatory cell influx, effective clearance of apoptotic cells and promotion of inflammatory cell egress. Defects in these processes promote the progression of atherosclerotic lesions into dangerous plaques, which can trigger atherothrombotic vascular disease, the leading cause of death in industrialized societies. In this Review I provide an overview of these concepts, with a focus on macrophage death and defective apoptotic cell clearance, and discuss new therapeutic strategies designed to boost inflammation resolution in atherosclerosis.

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Figure 1: A vulnerable atherosclerotic plaque showing the hallmarks of defective resolution of inflammation.
Figure 2: Examples of integration of inflammation resolution by resolution mediators.
Figure 3: Efferocytosis and inflammation resolution in early and advanced atherosclerosis.

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Acknowledgements

The author acknowledges stimulating conversations with E. A. Fisher, E. Thorp, D. Schrijvers, G. Randolph, L. Chan and A. Chawla during the conception and writing of this Review. The work from the author's laboratory cited here was supported by grants HL54591 and HL75662 from the US National Heart, Lung and Blood Institute.

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Glossary

Efferocytosis

The phagocytic clearance of apoptotic cells (from the Latin 'effero', meaning to take to the grave or bury) before they undergo secondary necrosis. The process usually triggers an anti-inflammatory response.

Alternatively activated macrophage

(M2 macrophage). A macrophage stimulated by IL-4 or IL-13 that expresses arginase 1, the mannose receptor CD206 and IL-4 receptor-α. There may be pathogen-associated molecular patterns expressed by helminths that can also drive the alternative activation of macrophages.

Atherosclerosis

A process whereby lipids, inflammatory cells and extracellular matrix accumulate in the subendothelial space (intima) of focal areas of medium-sized arteries, which finally leads to plaque formation.

Atherothrombotic vascular disease

(ATVD). Disease caused by acute occlusive arterial thrombosis overlying areas of chronic atherosclerosis. The occlusive thrombosis starves the tissue that the involved artery feeds of oxygen and nutrients. For example, if the involved artery feeds the heart muscle, myocardial infarction (death of heart muscle cells) can ensue.

Insulin resistance

A state in which signalling through insulin receptors is impaired. The cause can be exposure to high levels of insulin, which downregulates insulin receptors by a negative homeostatic mechanism, or disruption of signalling molecules downstream of the insulin receptor, such as insulin receptor substrate 1 (IRS1) and IRS2. Insulin resistance, caused by high levels of insulin in the bloodstream, is responsible for a substantial portion of the pathology associated with type 2 diabetes, including ATVD.

Atherosclerotic plaque

The name given to an atherosclerotic lesion without precise designation of lesion stage, but usually referring to a lesion that has developed beyond the early foam cell stage, particularly a lesion that is raised and fibrotic.

Atherothrombosis

Following the rupture of unstable atherosclerotic plaques, thrombogenic material becomes exposed or released to mediate thrombus formation and eventually occlusion of an artery.

Secondary necrosis

A process that occurs in apoptotic cells that are not cleared by phagocytes. The integrity of the plasma membrane is lost and the constituents of the cell are released.

Atheroma

An advanced atherosclerotic plaque, particularly one that is rich in cholesterol-filled macrophage foam cells and has areas of plaque necrosis.

Apolipoprotein E (Apoe)−/− mice

A widely used mouse model that is prone to develop atherosclerosis because the mice have high levels of types of atherogenic lipoprotein called remnant lipoproteins. This lipoprotein abnormality is cause by the genetic absence of apolipoprotein E (APOE), which normally clears remnant lipoproteins from the bloodstream by interacting with hepatocytes.

Endoplasmic reticulum (ER) stress

Perturbation of ER function, such as that which occurs during a high level of protein translation or when newly synthesized proteins become misfolded, resulting in the activation of a corrective signal transduction pathway called the unfolded protein response.

Low-density lipoprotein receptor (Ldlr)−/− mice

Another widely used mouse model of atherosclerosis. These mice accumulate high levels of low-density lipoprotein (LDL) when on a high-fat diet because their hepatocytes lack LDL receptors and cannot efficiently rid the bloodstream of atherogenic LDL particles.

Atherosclerotic lesion

A collection of lipids, cells and extracellular matrix in a focal area of the arterial subendothelium. These lesions are triggered by the accumulation of apolipoprotein B-containing lipoproteins and a maladaptive, macrophage-dominant inflammatory response to these lipoproteins. With further intracellular lipid accumulation and formation of foam cells, atherosclerotic plaques develop. The later-stage lesions contain a core of extracellular lipid surrounding the cholesterol-laden cells, many of which undergo apoptosis or necrosis.

Periodontal disease

A bacteria-mediated inflammatory disease of the gums that has an epidemiological association with atherothrombotic vascular disease, perhaps through promoting systemic inflammation.

Unfolded protein response

(UPR). A response that increases the ability of the endoplasmic reticulum (ER) to fold and translocate proteins, decreases the synthesis of proteins degrades misfolded proteins and corrects disturbances in calcium and redox imbalance in the ER. If prolonged, the UPR can trigger apoptosis.

Foam cell

A macrophage in the arterial wall that ingests cholesterol-rich apolipoprotein B-containing lipoproteins and thereby accumulates cholesteryl fatty acid esters. These cells secrete various substances involved in plaque growth.

Statins

A family of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), an enzyme that catalyses the conversion of HMG-CoA to L-mevalonate. These molecules are mainly used as cholesterol-lowering drugs, but they also have immunoregulatory and anti-inflammatory properties, the clinical significance of which is not fully known. L-mevalonate and its metabolites are implicated in cholesterol synthesis and other intracellular pathways.

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Tabas, I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol 10, 36–46 (2010). https://doi.org/10.1038/nri2675

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