Chapter 47 : Mechanisms of Myeloid Cell Modulation of Atherosclerosis

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Concepts of the pathogenesis of atherosclerosis have evolved substantially through the decades. Viewing it as an inevitable degenerative process, Sir William Osler attributed atherosclerosis to the stress and strain of modern life at the dawn of the 20th century ( ). Indeed, the pathogenesis of atherosclerosis had given rise to great controversy in the middle portion of the 19th century, particularly among German pathologists. Von Rokitansky postulated a role of incorporated thrombus into the artery wall as the primary event in atherosclerosis ( ). Rudolf Virchow posited a role for proliferation of medial cells, now recognized as arterial smooth muscle cells (SMCs), in the pathogenesis of atherosclerosis ( ). Virchow also recognized cell death as a component of atherogenesis and observed bone formation in atherosclerotic plaques. While von Rokitansky’s notion of the incorporation of thrombus lost popularity, the concept of atherosclerosis as a proliferative disorder of SMCs received considerable attention by pathologists and cell biologists in the latter part of the 20th century. Earl Benditt provided evidence for monotypic accumulation of SMCs in atherosclerotic plaques ( ). Russell Ross focused on the role of platelet products, notably platelet-derived growth factor, as a causal stimulus for SMC growth in atherosclerotic plaques ( ).

Citation: Swirski F, Nahrendorf M, Libby P. 2017. Mechanisms of Myeloid Cell Modulation of Atherosclerosis, p 813-824. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0026-2015
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Figure 1

Roles of myeloid cells in the evolution of the atherosclerotic plaque. This figure depicts the participation of myeloid cells in the evolution of the atheroma from the inception (left) through the progression and complication of the plaque (middle to right). Dendritic cells may populate the normal arterial intima. Early in the atherogenesis, monocytes adhere to endothelial cells (left). The adherent monocytes can diapedese into the intima and mature into macrophages. These cells imbibe lipid and become foam cells, a hallmark of the atheromatous plaque. These cells populate the lipid core of the evolving atheroma (yellow central potion, middle.) These foamy macrophages can elaborate many mediators that amplify and sustain the atherogenic process. In particular, they can secrete interstitial collagenases, members of the MMP family, that can degrade the collagen fibrils that lend strength to the fibrous cap that overlies the lipid core of the established atheroma. Cleavage of collagen in the plaque’s fibrous cap allows contact of the blood coagulation components with the procoagulant tissue factor produced by the plaque macrophages. Thus, disruption of the plaque by a fracture of the fibrous cap triggers thrombosis that leads to the most dreaded clinical complications of atherosclerosis such as the acute coronary syndromes and many ischemic strokes. Macrophages can die within plaques, as shown by the cell with the pyknotic nucleus casting off apoptotic bodies that can bear tissue factor. Macrophages can also release microparticles that can provide a nidus for spotty calcification associated with plaque instability. Calcium mineral can coalesce into plates that complicate the advanced atherosclerotic plaque. As plaques mature, they can become less cellular and accumulate more extracellular matrix. In regions of plaques rich in proteoglycan and glycosaminoglycans, endothelial cells can detach, exposing blood to underlying collagen and other thrombogenic mediators that can instigate clot formation. This process, denoted superficial erosion, can lead to recruitment of polymorphonuclear leukocytes (PMNs). Dying granulocytes release DNA that can associate with the pro-oxidant enzyme myeloperoxidase, the procoagulant tissue factor, and other enzymes associated with further endothelial damage and thrombosis. These NETs can further entrap platelets, promoting propagation of thrombi. The dendritic cells in plaques can present antigen to T cells, providing a link between innate and adaptive immunity. Mast cells in the adventitia of arteries can elaborate numerous mediators including histamine, heparin, serine proteinases, and cytokines that can amplify atherogenesis and lesion complication. Thus, myeloid cells participate in all phases of atherogenesis, from lesion initiation (left) through thrombotic complications (middle and right).

Citation: Swirski F, Nahrendorf M, Libby P. 2017. Mechanisms of Myeloid Cell Modulation of Atherosclerosis, p 813-824. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0026-2015
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Figure 2

Monocyte and macrophage diversity in relation to cardiovascular homeostasis. Blood monocytes derive from hematopoiesis in the bone marrow or from extramedullary hematopoiesis in the spleen that harbors a preformed pool of proinflammatory monocytes in mice. Monocytes enter tissues in response to chemoattractants that engage the chemokine receptors CCR2, CCR5, and CX3CR1. Hematopoietic growth factors, notably CSF-1 (M-CSF), promote the maturation of monocytes into tissue macrophages. Once recruited to and resident in tissues, macrophages can polarize toward a proinflammatory set of functions including production of cytokines such as TNF or IL-1 isoforms. IRF5 provides an example of a transcription factor that promotes the polarization of macrophages toward the proinflammatory palette of functions. The transcription factor NF-κB regulates the genes that encode a number of proinflammatory mediators elaborated by the proinflammatory subset of macrophages (pink box). Monocytes/macrophages can modulate toward a reparative and resolution-promoting set of functions under the influence of various transcription factors including nuclear receptor subfamily 4 group a member 1 (NR4a1), also known as Nur77. Mediators elaborated by the reparative subset of macrophages include IL-10; vascular endothelial growth factor (VEGF), a stimulator of angiogenesis; and transforming growth factor β (TGF-β), an anti-inflammatory and fibrogenic protein. The balance between the proinflammatory versus anti-inflammatory, reparative, and resolution functions of macrophages determines critical aspects of atherogenesis and aspects of myocardial disease related to repair of ischemic injury and the responses to hemodynamic overload conditions, features of myocardial remodeling critical in determining clinical course including the development of heart failure. ROS, reactive oxygen species (e.g., superoxide anion and hypochlorous acid); RNS, reactive nitrogen species (e.g., nitric oxide).

Citation: Swirski F, Nahrendorf M, Libby P. 2017. Mechanisms of Myeloid Cell Modulation of Atherosclerosis, p 813-824. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0026-2015
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Figure 3

Distinctions between superficial erosion and fibrous cap rupture as causes of arterial thrombosis. Source: reference , with permission.

Citation: Swirski F, Nahrendorf M, Libby P. 2017. Mechanisms of Myeloid Cell Modulation of Atherosclerosis, p 813-824. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0026-2015
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Figure 4

A depiction of potential pathophysiologic pathways that yield superficial erosion and thrombosis on atherosclerotic plaques. The bottom of the diagram depicts a longitudinal section of an artery that harbors an extracellular matrix-rich atheroma. The darker brown indicates accumulation of the proteoglycans such as versican and biglycan and of the glycosaminoglycan hyaluronic acid. (1) Some possible triggers for endothelial damage that causes superficial erosion. Inciting stimuli could include pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), or other ligands for innate immune receptors, including Toll-like receptor 2 (TLR2). These ligands bind to pattern recognition receptors on the surface of the endothelial cell. Hyaluronan, a common constituent of plaques that have undergone superficial erosion, can activate TLR2. Various apoptotic stimuli elaborated by myeloid cells in plaques, as well as oxidized lipoproteins, can unleash endothelial apoptosis. Matrix-degrading enzymes including MMPs can catabolize constituents of the basement membrane that comprises a substrate for endothelial cell adherence via integrins or other adhesion molecules. The nonfibrillar collagenases MMP-2 and MMP-9 and the activator of MMP-2, MMP-14, enzymes that localize in atheromata, may cleave the tethers of the endothelial cell to the basement membrane. (2) Some of the downstream effects of erosion. Once an endothelial cell has sloughed (as portrayed by the endothelial cell with nuclear pycnosis), the moribund endothelial cell can spew forth microparticles rich in tissue factor, a potent procoagulant. Uncovering the subendothelial matrix stimulates sticking of granulocytes and their activation and degranulation. Granulocytes elaborate reactive oxygen species (ROS) such as hypochlorous acid, HOCI, produced by myeloperoxidase (MPO), as well as superoxide anion (O ). This scheme postulates arrival of granulocytes secondarily, only after the initial disturbance of the endothelial monolayer. Granulocytes can also release myeloid-related protein (MRP) 8/14, a calgranulin family member implicated in inflammation and other aspects of atherothrombosis. Agonal granulocytes release DNA and citrullinated histones that contribute to NETosis, the formation of NETs. NETs can promote propagation of thrombosis and entrap further myeloid cells and platelets that amplify regional inflammation. Exposure of the subendothelial extracellular matrix macromolecules can also activate platelets, triggering their degranulation and elaboration of proinflammatory mediators including IL-6 and RANTES. In addition, activated platelets release plasminogen activator inhibitor-1 (PAI-1), which inhibits endogenous fibrinolysis, stabilizing clots. PMN, polymorphonuclear leukocyte. Source: reference , with permission.

Citation: Swirski F, Nahrendorf M, Libby P. 2017. Mechanisms of Myeloid Cell Modulation of Atherosclerosis, p 813-824. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0026-2015
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