UvA-DARE (Digital Academic Repository) Cytokines in atherosclerosis… · foam cells, including oxysterols like oxLDL 38, oxygen radicals like nitric oxide 36 and several cytokines,

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Cytokines in atherosclerosis: an intricate balance

Boshuizen, M.C.S.

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Citation for published version (APA):Boshuizen, M. C. S. (2016). Cytokines in atherosclerosis: an intricate balance.

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Chapter 1

General Introducti on

13358- Boshuizen-Binnenwerk na proefdruk.indd 9 4-3-2016 16:17:13

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IntroductionThe improvement in quality of life has increased the average life-expectancy over the last few years in many parts of the world. This is, however, accompanied by a strong increase in diseases associated with ageing, such as neurodegenerative diseases, cancer and cardiovascular diseases (CVDs). CVD is the main global cause of mortality, with 17.3 million deaths per year, a number that is expected to grow rapidly 1. Atherosclerosis is the underlying pathology in the majority of clinical manifestations of CVD. Atherosclerotic disease progression is normally without any clinical symptoms. However, when clinical symptoms arise, they are mostly acute and can be the result of blood flow-obstructing stenoses or because of plaque rupture or erosion. Plaque rupture or erosion results in thrombus formation which can obstruct blood flow in the heart or in the brain, leading to myocardial infarction or stroke respectively 2.Several risk factors are known to promote atherogenesis and its clinical manifestations, of which smoking, dyslipidemia, hypertension and obesity strongly contribute to disease 3. With the incidence of obesity and the metabolic syndrome growing worldwide, a serious threat for the increased development of CVDs, including atherosclerosis, has emerged 4-6. Lipid-lowering strategies have thus far been the main therapeutic approach to reduce atherosclerosis 7, 8. But anti-inflammatory strategies now also seem promising in reducing atherogenesis in experimental settings 9. Currently, clinical trials are being performed in which the relevance of blocking inflammatory agents in atherosclerosis development are tested 10-12. However, these therapies will likely not be enough to fully eradicate atherosclerosis and its cardiovascular complications. As atherosclerosis is an extremely complex and multifactorial disease, better understanding of the disease process is needed to develop more successful therapies.

Atherogenesis Atherosclerosis is a complex lipid-driven inflammatory disease in which numerous cell types and inflammatory mediators are involved 13, 14. The initiating step in atherogenesis is endothelial dysfunction, which can be induced by shear stress or by traditional risk factors such as dyslipidemia or hypertension. A result of endothelial dysfunction is increased permeability to circulating lipoproteins, such as low-density lipoproteins (LDL) 15, 16. LDL particles accumulate in the intima, were they are prone to become modified, often resulting in oxidized LDL (oxLDL), which is the most abundant lipoprotein form present in atherosclerotic lesions 17. OxLDL on its turn induces inflammatory responses by further activating the endothelium by the expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), and by the expression of several cytokines and chemokines such as monocyte chemoattractant protein-1 (MCP-1) 2, 18. Consequently, monocytes are recruited to the arterial wall, where they migrate into the intima, differentiate into macrophages and ingest the modified lipoproteins 19, 20. This uptake is mainly regulated via scavenger receptor A and CD36 and leads to lipid-loaded foam cells 21, 22. Macrophages and foam cells are critical components of atherosclerotic lesions as they enhance inflammation via secretion of inflammatory cytokines and chemokines which recruits more inflammatory cells like monocytes, T cells and neutrophils 13, 23. Macrophages are very plastic cells, as they can switch from one phenotype to another thereby adopting different polarization states 24. Numerous factors in the plaque microenvironment can induce macrophage polarization, resulting in a very heterogenic cell population 25. A


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simplified classification describes that plaque-derived signals, like cytokines, can induce either a pro-inflammatory M1 macrophage phenotype or an anti-inflammatory M2 phenotype. M1 macrophages are elicited by stimulation with IFNγ or LPS and secrete several inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1β, IL-6 and IL-12, and produce reactive oxygen species. M2 macrophages can be induced upon stimulation with IL-4, IL-13 and IL-10 and respond by secretion of anti-inflammatory cytokines like IL-10 and TGF-β 19, 24. As can be deducted from these characteristics, M1 macrophages may promote atherosclerosis, while M2 macrophages may dampen atherosclerosis development. Different macrophage populations have been described in human atherosclerotic lesions 26. Interestingly, M1 macrophages were observed in the rupture-prone shoulder regions of plaques, while M2 macrophages were found in more stable plaque areas 27. Macrophage polarization may therefore be an important determinant of plaque stability.Besides macrophages, other immune cells also tightly regulate atherosclerosis development. Concerning innate immunity, neutrophils have received increasing attention during the last few years and they are now known to influence atherogenesis by the secretion of several pro-inflammatory mediators and by affecting plaque stability 28, 29. Dendritic cells (DCs) link innate and adaptive immunity and are found to accumulate in atherosclerotic lesions. However, different DC subsets have been identified which differ in their location and immune functions and thus also exert different actions throughout disease development 30. The adaptive immune system also strongly influences atherosclerosis development. On the one hand a pro-atherosclerotic role for T cells was initially described, when T cell deficient mice showed a strong decrease in lesion development 31. However, several T cell subsets are now identified, with varying pro- and anti-atherogenic properties. Some of those have already a well-described role in atherogenesis, while other subsets are just being discovered 32. On the other hand, B cells were initially described as being atheroprotective 33. However, upon the finding that the B cell population also consist of different subsets, different atherogenic effects were attributed to each subset 34, 35. With all those different immune cell subsets in mind, it is clear the immune response is central in controlling atherosclerosis development.When plaques advance, non-immune cells like vascular smooth muscle cells (VSMCs) come into play as well as they migrate from the media to the intima, where they form a plaque-stabilizing fibrous cap surrounding the pro-inflammatory core of the lesion. In addition, collagen is secreted to create further plaque stability 23. Plaque stability is challenged by the death of lesional macrophages as apoptotic macrophages expel their lipid content into the intima 36, 37. Several apoptosis inducers are known to play a role in apoptosis of lipid-loaded foam cells, including oxysterols like oxLDL 38, oxygen radicals like nitric oxide 36 and several cytokines, for instance the interferons 39-42. Those potential apoptosis inducers all have the property to activate caspases and to induce ER stress 43, 44. In early phases of atherosclerosis, apoptotic cells are efficiently phagocytosed by macrophages. However, when atherosclerotic lesions progress this clearance becomes inefficient as macrophages are already fully lipid-loaded. This results in secondary necrosis of the already death macrophages, leading to a plaque destabilizing necrotic core 38. The plaque fibrous cap and the necrotic core are the two most important determinants of plaque stability, which are both under the influence of inflammatory processes. So, the equilibrium between these lesional components and the inflammatory milieu determines plaque stability and thus, disease outcome.

Interferons In 1957 the interferons (IFNs) were the first cytokines to be described and were found to


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interfere with viral infection 45. Nowadays they are known as class 2 cytokines with various effects influencing both innate and adaptive immunity during numerous infections. They are considered to be important immunomodulatory cytokines, but in contrast to their protective capacities, interferons can also have detrimental effects on disease outcome 46-

48. Their role in disease is very context specific and depends among others on the cellular source of the interferons and the subsequent induction of specific interferon stimulated genes (ISGs), processes that thus should be tightly controlled. The interferons consist of 3 distinct family members. The type I interferon (T1 IFNs) family consist of several members of which IFNα and IFNβ are best characterized. T1 IFNs can be secreted by almost all cells, with the plasmacytoid dendritic cells (pDCs) being their main producers 46, 49. The only type II IFN (T2 IFN), IFNγ, is secreted by lymphocytes, activated macrophages and natural killer cells 50. The type III interferons were recently discovered and were found to have similar biological activity as the T1 IFNs. Most cells can secrete the type III IFNs but its receptor is mostly restricted to the epithelium 51. All three interferon families signal via a different heterodimeric receptor complex 52, 53, which is described in more detail in Chapter 2 54. IFN signaling results in induction of the expression of hundreds of ISGs, of which some are regulated by a single IFN family, while others are induced by all 3 classes of IFNs. Multiple connections exist between the different IFN families to induce a proper immune response 55, 56. For example, T1 IFNs can induce STAT1 homodimerization to stimulate IFNγ activated sequences, while T2 IFNs can activate the IFN-stimulated gene factor 3 complex to induce transcription of T1 IFN-target genes 57, 58.

Interferons in viral diseaseClassically, the T1 IFNs are known to be induced upon viral infections. The presence of viral components, mostly nucleic acids, triggers activation of pattern recognition receptors, such as toll-like receptors (TLRs), RIG-1-like receptors (RLRs) and NOD-like receptors (NLRs). These receptors are located either at the cell surface, in the cytosol or in endosomal compartments 59-62. Activation of those receptors results in rapid induction of T1 IFNs, which mostly requires the action of the transcription factors interferon regulatory factors (IRF) 3 and 7 63-66. The T1 IFNs are produced in the early phases of an infection, where pDCs are essential for their first production, while in later stages of infection other cell types produce T1 IFNs as well 49,

67. It has been shown that upon viral infection, 60% of the transcriptional activity of pDCs is associated with induction of T1 IFN genes 68. This rapid production of T1 IFNs is needed to hamper viral replication and spread either via direct production of ISGs such as myxovirus resistance 1 (MX1) and IFN-induced transmembrane proteins (IFITMs) 69, or via the indirect activation of antiviral functions of other cells such as macrophages, NK cells and T cells 70. As a result antigen presentation and cytokine production in innate cells is stimulated 71, while effector T cell responses are also enhanced 70. With those actions in mind, it is not surprising that several viruses have developed mechanisms to block T1 IFN antiviral activities 72, 73. Although the T1 IFNs have crucial antiviral actions, T1 IFNs can also have detrimental effects upon viral infection, which is among others mediated by the induction of immunosuppression 48, 74. In lymphocytic choriomeningitis virus (LCMV) and human immunodeficient virus (HIV) infections, the T1 IFNs exert protective effects during the early phases of infection. However, when these infections cannot be cleared and become chronic, persistent T1 IFN activity may become harmful. In chronic LCMV infections, T1 IFN activity induces the immunosuppressive cytokine IL-10 and the programmed cell death 1 ligand 1 (PDL1), which together suppress T cell function and therefore fail to clear infection 75, 76. HIV patients are


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known to have a T1 IFN signaling profile 77, which has recently been associated with an increase in lymphocyte suppression and apoptosis, thereby enhancing disease progression 78, 79. The immunosuppressive actions of the T1 IFNs might be part of a coping mechanism to reduce host morbidity.Even though IFNγ is less well known as an antiviral cytokine, IFNγ has been proven to be essential for antiviral immunity as well 80-82. During a viral infection, IFNγ can be induced by earlier produced cytokines such as the T1 IFNs, IL-12 and IL-18 83, 84. This process is tightly controlled as the T1 IFNs can also negatively regulate IFNγ production, which seems mediated by STAT1 levels 85. Upon production of IFNγ, several antiviral mediators are produced of which protein kinase dsRNA-regulated (PKR) is an essential one. PKR is known to block viral protein synthesis and to induce apoptosis to limit viral spread 86, 87. Altogether, an equilibrium must be present in which the appropriate production of interferons is required to neutralize viral infections. A concise overview of the actions of IFNs in viral disease is presented in figure 1a.

Interferons in bacterial diseaseAlthough the T1 IFNs were initially known to have potent antiviral activities, it is now appreciated that they have important antibacterial effects as well. Since T1 IFNs were quite long considered to be unimportant in bacterial infections, they received little attention here and a better understanding is still needed to determine how exactly the T1 IFNs act as antibacterial mediators. An already well-described phenomenon is the induction of T1 IFNs by macrophages and DCs upon TLR4 activation by lipopolysaccharide (LPS) 88-

90. The secreted T1 IFNs then signal in an autocrine fashion to induce the production of ISGs, including the gene encoding inducible Nitric Oxide Synthase (iNOS). Nitric oxide (NO) production is essential in antibacterial immunity as many bacteria are sensitive to NO-mediated killing and its induction by T1 IFNs has been known for many years now 91, 92. As in viral disease, the T1 IFNs might have either disease inhibiting or disease promoting effects in bacterial infections, but the exact regulation of disease outcome is still poorly understood 48, 93. Next to NO production, the production of IFNγ by Th1 cells and NK cells is suggested to be an important mediator in T1 IFNs-induced antibacterial activity 94. IFNγ has always been classified as an antibacterial mediator. Upon infection IFNγ is secreted by Th1 cells and NK cells, which among others skews macrophages to a pro-inflammatory M1 phenotype. Activated M1 macrophages secrete IL-12 and IL-18 to stimulate microbicidal effector functions, including enhanced phagocytosis and the production of reactive oxygen species such as NO 50. The relevance of NO production in macrophage defense mechanisms is widely recognized 95. However, for maximal microbicidal NO production, IFNγ priming of macrophages is needed to enhance responses to bacterial LPS 96-98. The need for this priming mechanism is demonstrated by the resistance of IFNγ receptor (IFNGR) deficient mice to LPS-induced shock 99. In addition, bacterial infection models have shown the importance of IFNγ, as deficiency of IFNGR or T-bet, the regulator of Th1 differentiation, resulted in increased susceptibility and an increased severity of infection 47, 100. This susceptibility to bacterial disease was confirmed in IFNγ and IFNGR-deficient patients as well 101, 102. Again, a balance between the T1 IFNs and IFNγ may be of importance, which can influence the outcome of for instance mycobacterial infections 103-105. A concise overview of IFNs actions in bacterial disease is presented in figure 1a.

Interferons in autoimmune diseaseAs mentioned above, the interferons are crucial mediators of cellular defense mechanisms.


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However, their actions can also result in autoimmunity. The T1 IFNs for instance have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Peripheral blood monocytes from patients with SLE show an increased T1 IFNs signature 106 and the T1 IFNs are known to stimulate disease induction and progression 107. In addition, SLE patients may have an up to 50-fold increased risk for CVDs, which is amongst others attributed to this increased T1 IFN signature 108-111. Currently, clinical trials are being performed in which IFNα- and IFNAR-blocking strategies are being evaluated 112. The agents tested so far have proven to be safe, however great caution is required regarding the risk for developing infections. With the crosstalk of the T1 and T2 IFNs in mind, IFNγ also plays an established role in SLE pathogenesis 113. IFNγ-blocking therapies, like for IFNα, have thus far received little attention in the fight against SLE, probably due to the increased susceptibility towards infections. Nevertheless, IFNγ-antibody treatment of patients with progressive multiple sclerosis (MS) did show delay in disease progression. This indicates that neutralizing IFNγ could be a potential new treatment in progressive MS, outweighing the possible increased risk for infections 114. In Crohn’s disease, where IFNγ plays a prominent role, IFNγ-targeting therapies have also proven to be successful as early signs of clinical efficacy have been observed 115, 116. In addition to the abovementioned autoimmune diseases, future research should point out whether other diseases, like rheumatoid arthritis, would benefit from interferon-targeted therapies as well. A concise overview of IFNs actions in autoimmune disease is shown in figure 1b.

Interferons as therapeutic agents In contrast to the detrimental role for the T1 IFNs in autoimmunity, IFNβ is used as an effective treatment against relapsing remitting MS. This treatment has been shown to reduce MS relapses and delay the onset of progressive MS 117, 118. In hepatitis C virus (HCV) IFNα therapy has been the standard treatment for many years now, even though its effectiveness is rather limited. A shift in treatment regimen from interferon-based treatments towards more direct anti-viral therapies is now suggested as this seems to be more effective 119-

121. Also in myeloproliferative diseases and other types of cancer the T1 IFNs have been used as successful treatments 122, 123. The induction of an immune response to tumors by IFNγ and IFNγ’s anti-proliferative effects have been the subject in several clinical cancer trials as well 124, 125. Despite these beneficial indications, several attempts to treat cancer with recombinant IFNγ have so far resulted in mixed effects. This suggests that IFNγ can have both cytotoxic as well as cytoproliferative actions, likely depending on its surrounding environment 126. Because of IFNγ’s numerous inflammatory actions, this cytokine has clinically been tested as a treatment for several other diseases as well, including tuberculosis, invasive fungal infections and in HCV 127, 128. Despite all the valuable therapeutic applications of the interferons, it is important to keep their many immunomodulatory actions in mind, as those might influence the patients’ immune response.


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Figure 1. Overview of interferons in host protection and autoimmunity. a). Upon infection, infected cells produce IFNs, resulting in the expression of interferon stimulated genes (ISGs) in both infected and neighboring cells. One of the functions of ISGs is to limit the spread of infectious particles. Upon IFN stimulation or after sensing of infectious particles with pattern-recognition receptors (PRRs), macrophages and dendritic cells (DCs) also start producing IFNs and ISGs. In addition, they respond by increased antigen presentation and by the production of inflammatory mediators. Adaptive immunity is also influenced by the IFNs as effector functions of B and T cells


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are enhanced. b). The chronic IFN production that is present in several autoimmune diseases is continued in part by persistent stimulation of antigen-presenting cells, including macrophages and plasmacytoid dendritic cells (pDCs), by self antigens and damage-associated molecular pattern molecules (DAMPs). Continued IFN production increases T and B cell effector function, leading to autoantibody production, resulting in the characteristic tissue injury. Chronic stimulation by IFNs also increases production of IL-10 by innate immune cells such as macrophages, which suppresses inflammatory responses, likely to reduce host morbidity. IFNAR, interferon α/β receptor; Ag presentation, antigen presentation; NO, nitric oxide.

Interferons in atherosclerosisThe interferons are also known to play a substantial role in atherosclerosis. A growing body of evidence is present showing that the interferons act as pro-atherosclerotic mediators 41,

54, 129-139. Studies on the role of the T1 IFNs in atherosclerosis development have only just started, while the role of IFNγ in atherosclerosis is already longer established. Their actions are prominent throughout both the initiation and progression of the disease as they are for instance known to promote leukocyte recruitment towards atherosclerotic lesions and to stimulate lesional apoptosis 54. The way in which the interferons influence atherosclerosis development is extensively described in Chapter 2. In any case, the actions of this family of cytokines in atherogenesis are extremely complex, and the way in which they mediate atherosclerosis development can therefore be considered to be an intricate balance.

Interleukin-10Interleukin-10 (IL-10) is, like the interferons, a class 2 cytokine. It was discovered in 1989 as a cytokine that inhibits the production of pro-inflammatory cytokines by Th1 cells 140. Indeed, mice deficient in IL-10 have increased Th1 cell responses, resulting for instance in enhanced bacterial clearance upon infection 141, 142. Subsequently, it was found that IL-10 affects not only Th1 cells but several immune cells, like macrophages and DCs, thereby dampening inflammatory responses 143, 144. IL-10 is produced by nearly all leukocytes, adding to the complexity of this immunomodulatory cytokine 52, 144. T regulatory cells (Tregs) use IL-10 as their hallmark cytokine to limit inflammation and autoimmunity and nowadays B regulatory cells (Bregs) are investigated for their role in self-tolerance via the usage of IL-10 145, 146. Another important function of IL-10 is the suppression of antigen presentation by macrophages and DCs via an autocrine feedback loop 140, 147. As an essential immunosuppressive cytokine, IL-10 thus limits inflammatory responses at different levels in both innate and adaptive immunity.IL-10’s actions are mediated after binding to its cell surface receptor, IL-10R, which consist of two chains, IL-10R1 and IL-10R2. In response to IL-10 binding, signal transducer and activator of transcription (STAT)3, STAT1 and STAT5 are recruited to the receptor complex where they become phosphorylated for their activation. Homo- and heterodimers of these STAT molecules translocate to the nucleus to drive gene transcription of for instance suppressors of cytokine signaling (SOCS)-1 and SOCS-3 143. SOCS-1 is a negative regulator of inflammatory cytokine production and thus an important IL-10 target 148. Another mechanism by which IL-10 suppresses inflammation is by inhibition of NFκb activity, a transcription factor necessary for inflammatory cytokine production 149.IL-10-directed therapies have been tested in several clinical trials to treat autoimmune diseases. An important role for IL-10 in intestinal homeostasis has been described, which is impaired in inflammatory bowel disease (IBD) 150, 151. Despite protective effects of IL-10 in mouse intestinal inflammation models, clinical trials using IL-10 therapy in IBD have mainly been negative 144, 152. IL-10 administration in MS, where reduced secretion of IL-10 by Bregs


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has been reported, also appeared ineffective 144, 153. In contrast to deficient production of IL-10 in several autoimmune diseases, overproduction of IL-10 by monocytes and B cells has been implicated in SLE disease pathogenesis 154. Here, neutralization of IL-10 has shown potential in a small cohort of SLE patients 155. But altogether, therapeutic targeting of IL-10 in autoimmune diseases still seems elusive as its widespread immunomodulatory actions are highly complex.

IL-10 in atherosclerosisWith the strong anti-inflammatory properties of IL-10 in mind, IL-10 is thought to act in an anti-atherogenic manner. IL-10 has been identified in the human atherosclerotic lesion, where it seems to modulate the inflammatory response and protect from too much apoptotic cell death 156. Since this discovery, IL-10 has been a target for intervention in experimental atherosclerosis. These experimental data further confirmed the anti-atherogenic role for IL-10, as deficiency of IL-10 157, 158 or of its downstream signaling molecules 159, 160 promoted atherosclerosis, whereas gene therapy for IL-10 161-164 decreased atherosclerosis development. These observed atheroprotective effects of IL-10 are not only attributed to anti-inflammatory activities, but also to its regulation of macrophage lipid handling. IL-10-mediated effects on cholesterol metabolism are primarily linked to increased cholesterol efflux, resulting in decreased macrophage foam cell formation 165, 166. In addition, IL-10 is also involved in stabilization of the atherosclerotic lesion as it provides pro-survival factors to leukocytes 156, 163, 167 and limits extracellular matrix degradation 157, 158, 168. Altogether, IL-10 can thus indeed be considered as an anti-atherogenic mediator. But as its atheroprotective actions are tightly controlled and still not fully understood, future research is needed to investigate the potential of IL-10-based therapies in atherosclerosis.

Aim of thesisIn recent years progress has been made in understanding the contribution of the interferons and IL-10 in both immunity and atherosclerosis, as can be deducted from the above mentioned sections. Accumulating in vitro and in vivo research indicates that the interferons can be considered as pro-atherosclerotic cytokines, whereas IL-10 is considered to be anti-atherogenic. Nevertheless, their atherosclerotic actions are very complicated and tightly balanced. More research is therefore needed to fully elucidate their atherosclerotic effects. To this end, the aim of this thesis is 1) to assess the functional contribution of interferons in atherogenesis with regards to foam cell formation and foam cell inflammatory responses and 2) to investigate whether interferon and IL-10 modulation can be used to diminish atherosclerosis.

Chapter 2 provides an overview regarding the role of interferons in atherosclerosis and discusses whether interferons could be regarded as new molecular targets in atherosclerosis treatment. In Chapter 3 the effects of IFNβ on macrophage foam cell formation are characterized, as to date a direct link between the T1 IFNs and this essential atherosclerotic process is still missing. We could demonstrate that IFNβ promotes macrophage foam cell formation by increasing SR-A-mediated cholesterol influx and decreasing ABCA1-mediated efflux. In Chapter 4 the role of IFNβ in foam cell inflammatory responses is assessed, as lipid loading of monocytes and macrophages resulted in downregulation of interferon signaling pathways. This made us question whether this also results in a decreased interferon response and a decrease in the accompanying inflammatory response. We observed macrophage


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hyporesponsiveness towards IFNβ under high cholesterol conditions, which might be relevant for IFNβ-mediated inflammatory activities. In Chapter 5 blockade of the IFNα/β receptor subunit 1 was investigated in a combined mouse model for atherosclerosis and arteriogenesis. We were able to stimulate arteriogenesis without enhancing atherosclerosis burden in our mice, which had been a downside of previous pro-arteriogenic stimuli so far. The pro-atherosclerotic role of IFNγ was already established many years ago. In vivo atherosclerosis studies to date focused on the systemic role of IFNγ, making it impossible to conclude which cell types exactly are involved here. Therefore we examined the effects of IFNγ on myeloid cells in atherogenesis, which is described in Chapter 6. From this study we could conclude that myeloid IFNγ signaling is dispensable for atherosclerosis development. A similar rationale formed the basis for the study described in Chapter 7. In this chapter the role of myeloid specific IL-10 signaling in atherosclerosis was studied. So far, the anti-atherogenic role of IL-10 was already well established, but the contribution of cell-specific effects still remained unclear. We could show that myeloid cells do not contribute to the atheroprotective actions of IL-10 and that myeloid IL-10 signaling even acts pro-atherogenic. In addition, we observed a new link between myeloid IL-10 signaling and cholesterol metabolism. Finally, in Chapter 8 all results obtained in this thesis and its implications are summarized and discussed.

References1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C and Stroke Statistics S. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2015;131:e29-322.2. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. The New England journal of medicine. 2005;352:1685-95.3. Ezzati M, Obermeyer Z, Tzoulaki I, Mayosi BM, Elliott P and Leon DA. Contributions of risk factors and medical care to cardiovascular mortality trends. Nature reviews Cardiology. 2015.4. Alexopoulos N, Katritsis D and Raggi P. Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis. Atherosclerosis. 2014;233:104-12.5. Luna-Luna M, Medina-Urrutia A, Vargas-Alarcon G, Coss-Rovirosa F, Vargas-Barron J and Perez-Mendez O. Adipose Tissue in Metabolic Syndrome: Onset and Progression of Atherosclerosis. Archives of medical research. 2015;46:392-407.6. Rocha VZ and Libby P. Obesity, inflammation, and atherosclerosis. Nature reviews Cardiology. 2009;6:399-409.7. Ferrieres J. Effects on coronary atherosclerosis by targeting low-density lipoprotein cholesterol with statins. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2009;9:109-15.8. Nicholls SJ, Borgman M, Nissen SE, Raichlen JS, Ballantyne C, Barter P, Chapman MJ, Erbel R and Libby P. Impact of statins on progression of atherosclerosis: rationale and design of SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: effect of Rosuvastatin versus Atorvastatin). Current medical research and opinion. 2011;27:1119-29.9. Moubayed SP, Heinonen TM and Tardif JC. Anti-inflammatory drugs and atherosclerosis. Current opinion in lipidology. 2007;18:638-44.10. Back M and Hansson GK. Anti-inflammatory therapies for atherosclerosis. Nature reviews Cardiology. 2015;12:199-211.11. Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, Gupta M, Clearfield M, Libby P, Hasan AA, Glynn RJ and Ridker PM. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. American heart journal. 2013;166:199-207 e15.12. Ridker PM, Thuren T, Zalewski A and Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). American heart journal. 2011;162:597-605.13. Hansson GK and Libby P. The immune response in atherosclerosis: a double-edged sword. Nature reviews


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165. Halvorsen B, Holm S, Yndestad A, Scholz H, Sagen EL, Nebb H, Holven KB, Dahl TB and Aukrust P. Interleukin-10 increases reverse cholesterol transport in macrophages through its bidirectional interaction with liver X receptor alpha. Biochemical and biophysical research communications. 2014;450:1525-30.166. Han X, Kitamoto S, Lian Q and Boisvert WA. Interleukin-10 facilitates both cholesterol uptake and efflux in macrophages. The Journal of biological chemistry. 2009;284:32950-8.167. Han X, Kitamoto S, Wang H and Boisvert WA. Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2010;24:2869-80.168. Holven KB, Halvorsen B, Bjerkeli V, Damas JK, Retterstol K, Morkrid L, Ose L, Aukrust P and Nenseter MS. Impaired inhibitory effect of interleukin-10 on the balance between matrix metalloproteinase-9 and its inhibitor in mononuclear cells from hyperhomocysteinemic subjects. Stroke; a journal of cerebral circulation. 2006;37:1731-6.


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