**Inflammatory Mechanisms in Atherosclerosis**

**Inflammatory Mechanisms in Atherosclerosis**

DOI: 10.5772/intechopen.72222

#### Ida Gregersen and Bente Halvorsen Additional information is available at the end of the chapter

Ida Gregersen and Bente Halvorsen

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72222

#### **Abstract**

Atherosclerosis is a disease of chronic inflammation, characterized by a dysfunctional interplay between the immune apparatus and lipids. Immune cells, as well as nonimmune cells, drive plaque inflammation through a complex crosstalk of inflammatory mediators. The cells are activated by risk factor–induced triggers, which are present in the circulation and in the vessel wall, such as shear stress, oxidized lipoproteins and oxidative stress. Without relief from risk factors, the activation of inflammatory processes persists, resulting in a chronic nonresolving inflammation. Inflammation is associated with severity of disease, and complex lesions, which are prone to rupture and cause acute events, are characterized by extensive inflammation. Thus, inflammation is an active driver of atherosclerotic plaque development and a risk factor for atherosclerotic events. It is therefore of utmost importance to understand the mechanisms behind these inflammatory processes and to be able to develop new diagnostics and treatment modalities for atherosclerotic disorders. This chapter provides a brief overview of the most important inflammatory players and processes during atherosclerotic plaque development and of possible therapeutic targets to combat atherosclerotic disease.

**Keywords:** inflammation, monocytes, macrophages, T cells, cholesterol

## **1. Introduction**

Atherosclerosis is a complex disease of the artery wall. It is the major cause of cardiovascular disease (CVD), which is the most common cause of death in the world, killing 17.5 million people each year [1]. Although previously thought of as a disorder of age and cholesterol, it is now commonly appreciated that atherosclerosis results from a complex interplay between inflammation and lipids. As early as in the nineteenth century, Rudolf Virchow described inflammation as an active driver of plaque development; however, the importance of these findings was not appreciated until over a century later. During this time, modern immunology

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© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

evolved extensively and paved the way for in-depth understanding of how the immune system works. Identification of adhesion markers on endothelial cells and thus the ability of leukocytes to migrate into atheromas gave plausibility of inflammation as a contributor in atherogenesis [2, 3]. Furthermore, findings showing that monocytes [4], and later on that vascular cells [5, 6], secrete inflammatory mediators were important evidence supporting this. These discoveries were followed by clinical proof in the 1990s. Immune activation in atherosclerotic plaques was identified [7], and myocardial infarction was recognized as a potent trigger of CRP release [8]. Since then, an extensive number of animal as well as clinical studies have established inflammation as a major driver of atherosclerotic disease. Regardless of this acceptance, our understanding of atherogenic inflammation is far from complete.

chronic inflammation. There is, however, not only the quantity but also the phenotype of the macrophages that is important to the fate of the plaque [15]. The terms M1 and M2 describe the "classical" activated macrophage induced by T helper cell (Th) 1 cytokine interferon (IFN) γ and the "alternatively" activated macrophage induced by Th2 cytokines IL-13 and IL-4, respectively. In short, the M1 macrophages produce pro-inflammatory cytokines and chemokines, cause tissue injury and promote atherosclerotic plaque development. M2 macrophages are often divided into "wound healing" and "regulatory" macrophages, the latter induced by immune complexes and IL-10, and produce anti-inflammatory cytokines and increase plaque stability [16]. Their pro- and antiatherogenic role is supported by studies showing that plaques enriched in M2 macrophages are associated with a stable or regressive phenotype and vice versa. Growth factors, lipids and cytokines produced by vascular cells and immune cells in the plaque affect the macrophage polarization state. Due to the complexity of inflammatory stimuli present in the plaque, the terms "M1" and "M2" and "classical" and "alternative" are overly simplified, and it is more likely that there exists a range of overlapping phenotypes in the atherosclerotic lesions

Inflammatory Mechanisms in Atherosclerosis http://dx.doi.org/10.5772/intechopen.72222 33

Another cell of the innate immune system, with great importance for atherosclerotic plaque inflammation, is the dendritic cell (DC). Increased number of DCs is present in atherosclerotic plaques of both humans and mice, and also, as described later, in tertiary lymphoid organs in the adventitia. However, the circulating number of DCs has, by the majority of studies performed, been reported to be reduced in atherosclerosis, which could reflect hampered production from the bone marrow as well as increased recruitment to the plaque [20–22]. As macrophages, the DCs engulf lipids and become foam cells, thereby contributing to plaque development. On the contrary, it has also been suggested that DCs can control cholesterol homeostasis and counteract hypercholesterolemia. It is, however, their role as antigen presenting cells (APCs) that is most described in plaque inflammation [22]. Antigen presentation to T cells occurs both inside the plaque and in the lymphatic tissue, and it is shown that DCs can leave the atherosclerotic lesion upon signals from the chemokines CCL19 and CCL21 [23]. The different subgroups of DCs activate pro- and anti-inflammatory functions in T cells. Difficulties in finding DC-specific markers, as well as the broad spectrum of different DC cell subtypes, have complicated the study of DCs in atherogenesis. There is, however, without

Neutrophils, mast cells and innate lymphoid cells, such as natural killer (NK) cells, are also important contributors to inflammation in atherogenesis, and their role is increasingly appreciated. The description of these cell types is beyond the scope of this chapter, but has been

CD4+ Th cells are the most abundant of the adaptive immune cells in the plaque and are therefore the most studied. In the plaque, they are activated by epitopes of native as well as oxidative

*2.1.2. Dendritic cells are professional antigen presenting cells in the plaque*

doubt that DCs are important players in atherosclerotic disease [22, 24].

*2.1.3. Other innate immune cells in atherogenesis*

reviewed elsewhere [25–28].

*2.1.4. T-cell diversity in atherogenesis*

[15, 17–19].
