Sepsis is a life-threatening condition caused by a dysregulated host response to infection, it is associated with significant morbidity, mortality, and with a high financial burden on global... Show moreSepsis is a life-threatening condition caused by a dysregulated host response to infection, it is associated with significant morbidity, mortality, and with a high financial burden on global healthcare systems. Bacterial infections are the primary cause of sepsis, but the growing prevalence of antimicrobial resistance complicates the effectiveness of antimicrobial treatments. Moreover, limited understanding of the host immune response during sepsis hinders the discovery of valuable biomarkers and drug targets. As such, there is an urgent need to improve the treatment of sepsis. To tackle this challenge, we have concentrated our efforts on optimizing current treatment strategies and on facilitating the discovery of novel host inflammatory response directed therapeutics. In this thesis, we have utilized quantitative pharmacological modeling approaches to assess the adequacy of current dose regimens and to evaluate antibiotic pharmacokinetic variability, thereby optimizing antimicrobial therapies for sepsis. Additionally, our researches had aimed to deepen our understanding of the underlying dynamics of sepsis pathology, enabling the identification of promising biomarkers and therapeutic targets for sepsis. Our work demonstrated how quantitative modeling strategies can support the design of optimized treatment strategies, and how systematic model-based integration of disease mechanisms can help to overcome the translational challenges in sepsis drug development. Show less
Lipid signaling is an essential biological event/process in a plethora of pathophysiological conditions. The underlying idea of this thesis is that many of the roles and the complex interplay of... Show moreLipid signaling is an essential biological event/process in a plethora of pathophysiological conditions. The underlying idea of this thesis is that many of the roles and the complex interplay of the individual signaling lipids in inflammatory processes and related conditions in health and disease is not well known, and therefore has to be studied integrally as a complex network. In order to study this complex interplay, an improved broad analytical method is necessary to analyze a wide range of different signaling lipid classes such as oxylipins, (nitro) free fatty acids, endocannabinoids, bile acids and different subclasses of lysophospholipids. Therefore, the aim of this thesis is to develop a better method to study signaling lipids, and to apply it to study the role of these molecules in several relevant biological questions for a better understanding of inflammation related pathophysiology including autoimmune diseases, neurodegeneration and regulatory effect of exercise training. Show less
To increase clinical success rate of drugs, a better understanding of drug action mechanism and disease dynamics is required. Metabolomics, which studies small molecules involved in biochemical... Show moreTo increase clinical success rate of drugs, a better understanding of drug action mechanism and disease dynamics is required. Metabolomics, which studies small molecules involved in biochemical processes in organisms, has shown to be a useful tool for this better understanding. In this thesis, we focus on the endocannabinoid system (ECS) and profiling its related metabolic pathways using liquid chromatography - mass spectrometry (LC-MS) based metabolomics techniques. The endocannabinoid system (ECS) is a signaling system involved in multiple physiological and pathological processes. Due to its wide distribution and complex network of metabolic interactions, the development of drugs targeting the ECS has seen high failure rates. To get a better understanding of the behavior of the ECS and related pathways, LC-MS platforms with wide coverage of the major ECS-related metabolites, or with high sensitivity that reaches low levels of metabolites, were developed and optimized. Furthermore, these metabolomics platforms were applied in clinical studies looking into cardiometabolic health, and revealed correlations between endogenous metabolite signaling, cardiometabolic health and the benefits of exercise. Show less
Acute cardiovascular clinical events such as myocardial infarction and cerebral stroke represent the major cause of death in Western societies. These pathologies are primarily resulting from... Show moreAcute cardiovascular clinical events such as myocardial infarction and cerebral stroke represent the major cause of death in Western societies. These pathologies are primarily resulting from atherosclerosis, a progressive condition characterized by the accumulation of lipids, immune cells, and fibrous elements in large arteries. The pathogenesis of atherosclerosis involves complex interactions between a wide variety of cells, including monocytes, macrophages, neutrophils, and lymphocytes. It is essential to identify novel targets for therapeutic application in order to reduce the residual atherosclerotic cardiovascular disease risk in current and future patients. Recent studies have suggested that members of the protein arginine methyltransferase (PRMT) family can potentially serve as novel therapeutic targets for atherosclerosis because of their regulatory role in inflammation and metabolism. To validate the contribution of PRMTs in the progression of atherosclerosis, in the studies presented in this thesis we have investigated the effect of inhibition of PRMT functionality on atherosclerosis susceptibility in established atherosclerotic mouse models.To address the role of PRMTs in atherosclerosis, we therefore made use of specific PRMT inhibitors, i.e. TC-E 5003 for PRMT1 inhibition, TP-064 for PRMT4 inhibition, and GSK3326595 for PRMT5 inhibition, that thus far have primarily been applied in vivo in the context of cancer treatment. Show less
The external tissues of plants and animals are colonized by microbial communities termed microbiota. When organisms are exposed to environmental pollutants, these substances will therefore... Show moreThe external tissues of plants and animals are colonized by microbial communities termed microbiota. When organisms are exposed to environmental pollutants, these substances will therefore encounter microbiota at the exposure interface. Many antimicrobial substances have been found to disturb beneficial interactions between microbiota and the host, thereby impairing host health. Nanomaterials exhibit nanoscale properties that could affect host health in two additional, understudied, microbiota-dependent ways. Firstly, owing to their large surface area, adsorption interactions between nanomaterials, microbial metabolites and microbes could alter the identity and colloidal stability of nanomaterials, and may influence the dispersal of microbes. Secondly, the immuno-modulatory effects of microbiota could affect the sensitivity of hosts to immunotoxic nanomaterials. In this dissertation, we use a combination of computational techniques and zebrafish larvae experiments to unravel and quantify these interactions. We predict the affinity of microbial metabolites to carbon and metal nanomaterials, and show that titanium dioxide nanoparticles can affect the dispersal of microbes through aquatic ecosystems, and across different life stages of oviparous animals. Additionally, we provide insight into microbiota-dependent signaling pathways that affect the sensitivity of zebrafish larvae to particle-specific, immunotoxic effects of silver nanoparticles. Altogether, these results contribute to mechanistic pathways for microbiota-inclusive nanomaterial safety assessment. Show less
Depression shows a large heterogeneity of symptoms between and within persons over time. However, most outcome studies have assessed depression as a single underlying latent construct, using the... Show moreDepression shows a large heterogeneity of symptoms between and within persons over time. However, most outcome studies have assessed depression as a single underlying latent construct, using the sum score on psychometric scales as a total indicator for depression severity. The present dissertation aimed to expand our knowledge of depression by researching its symptom-specific longitudinal characteristics, its predictive factors, and methods for predicting depression and anxiety while taking individual symptoms into account. We demonstrated that individual depressive symptoms are not synchronized over time within patients and in groups of patients. We found that individual symptoms of depression are associated to different risk factors, as preceding chronicity, neuroticism, and inflammation were related to individual symptoms with vastly different magnitudes. Taken these findings together we have demonstrated that depressive disorder can not be characterized as an unified syndrome. Addressing depression at the syndrome level may obscure insights into both patient and symptom-specific characteristics. Our findings strengthen the idea that employing a symptom-focused approach in both clinical care and research is of value. With this dissertation, we hope to have contributed to the development of alternative ways to define and study depression and its symptoms. Show less
The vascular system delivers oxygen and nutrients through the entire body. In addition, it enables distribution of hormones and immune cells. A proper functioning vascular system is important in... Show moreThe vascular system delivers oxygen and nutrients through the entire body. In addition, it enables distribution of hormones and immune cells. A proper functioning vascular system is important in preventing cardiovascular disease (CVD). In recent years, several risk factors, e.g. smoking and obesity, have been described. Also genetic variants have been shown to influence vascular function and thereby the risk on developing CVD.In this thesis the role of Neuroimmune Guidance Cues (NGCs) in the development of atherosclerosis, one of the main causes of CVD is investigated. The development of atherosclerosis is characterized by the deposition of fatty acids and immune cells in the vessel wall. With several experiments we have shown that NGCs play an important role in the vessel wall and regulate atherosclerosis-related processes. We show that PLXNA4 regulates endothelial permeability, while the Eph receptor B2 regulates migration of monocytes through the vessel. In addition, we have shown that genetic variants in Eph receptor B4, EphrinB2 and Netrin-1 can modulate atherosclerosis-related processes and thereby could influence the development of CVD.The results shown here give us new insights in the function of the vascular system and provide novel targets to treat and/or prevent CVD. Show less
Herniation of the lumbar disc can cause severe pain radiating down the leg alongside a dermatome. This pain can be caused by compression of the nerve root, but recent evidence has indicated that a... Show moreHerniation of the lumbar disc can cause severe pain radiating down the leg alongside a dermatome. This pain can be caused by compression of the nerve root, but recent evidence has indicated that a local inflammation response may also play a role. This thesis focuses on how macrophages that infiltrate the herniated disc in patients with lumbar disc herniation, influence pain and recovery after discectomy. Our data shows that for most patients, if macrophages are present, they benefit the process of healing by leading to a quicker resorption of the herniated material which results in faster recovery. However, for patients with Modic changes, which indicates a degenerated endplate (structure between disc and vertebrae), the presence of macrophages is less beneficial, for they recover more slowly after surgery. The reason for this discrepency seems to be an altered differentiation profile in macrophages. Macrophages differentiate into different types with different behaviours: the M2 macrophages are known for its anti-inflammatory properties and tissue resorption. Our study found M2 macrophages in lower numbers in patients with degenerated endplates, which can explain their slower recovery. Together the data indicates that macrophage differentiation profiles in lumbar herniated discs are promising treatment targets. Show less
As HLA Class I expression is an important target for cytotoxic T cells but an in inhibitor of NKcells, we were interested in the regulation of its expression.We review HLA expression in UM, how it... Show moreAs HLA Class I expression is an important target for cytotoxic T cells but an in inhibitor of NKcells, we were interested in the regulation of its expression.We review HLA expression in UM, how it is involved in the inflammatory phenotype, how it is regulated and how putative treatments might be effective in its expression.We investigate the potential role of the NFkB pathway in the regulation of inflammation in UM and its potential association with HLA Class I expression.In order to increase our understanding for the reason behind the elevated HLA Class I expression in UM tumours, we investigate the involvement of epigenetics. We focus on a set of epigenetic enzymes called histone deacetylases and report that these regulators are highly expressed in Monosomy 3 UM.We wonder whether HDAC expression is influenced by the presence of infiltrating lymphocytes and macrophages.We focus on miRNA’s as another set of epigenetic regulators of inflammation. We investigate the potential relation of a set of 125 miRNA’s with HLA Class I expression and the presence of an infiltrate in UM and report two patterns of miRNA expression.We study the LAG3 immune checkpoint in UM tumours. As immune checkpoints might be responsible for the T cell exhaustion which is observed in UM, we investigate the involvement of LAG in prognostication and study how LAG3 and its ligands are distributed among different UM tumours. Show less
Hart- en vaatziekten zijn wereldwijd de belangrijkste doodsoorzaak, waarvan het grootste deel kan worden toegeschreven aan coronairlijden. De belangrijkste veroorzaker hiervan is atherosclerose... Show moreHart- en vaatziekten zijn wereldwijd de belangrijkste doodsoorzaak, waarvan het grootste deel kan worden toegeschreven aan coronairlijden. De belangrijkste veroorzaker hiervan is atherosclerose ofwel aderverkalking, wat een op zichzelf staande complexe lipide-gedreven chronische inflammatoire ontstekingsziekte is. Na een hartinfarct is tijdige reperfusie door een acute dotterbehandeling het belangrijkste doel om verdere schade aan de hartspier te beperken. Echter, het herstel van de coronaire perfusie zelf induceert myocardiale reperfusieschade. Gedurende vele jaren heeft translationeel onderzoek zicht gericht op immunomodulatie van deze post-ischemische inflammatierespons. Dit proefschrift omvat pre-klinisch onderzoek waarin gunstige modulatie van de post-ischemische inflammatierespons door farmacologische interventies met annexine A5 en phosphorylcholine antilichamen wordt aangetoond. Remming van bijvoorbeeld cytokine IL-6 en afweercellen als monocyten, macrofagen en leukocyten, resulteert na een hartinfarct in minder schade aan de hartspier met een verbetering van de resterende hartfunctie. Daarnaast werd onderzocht hoe een pre-klinisch experimenteel onderzoeksmodel kan worden geoptimaliseerd door rekening te houden met zowel ischemie-reperfusie schade als hypercholesterolemie, een belangrijke risicofactor voor hart- en vaatziekten. Door gebruik te maken van klinisch relevantere onderzoeksmodellen kunnen in de toekomst hopelijk meer veelbelovende pre-klinische onderzoeksresultaten succesvol worden vertaald naar de dagelijkse klinische praktijk. Ter introductie worden deze onderzoeksresultaten voorafgegaan door een state-of-the-art review waarin een overzicht wordt gegeven van alle fases die deze post-ischemische inflammatierespons omvat. Hierbij worden de meest toonaangevende onderzoeksresultaten betreffende modulatie van deze inflammatierespons beschreven. Na recente succesvolle grote klinische trials, zal in de toekomst een belangrijke rol zijn weggelegd voor modulatie van deze afweerreactie bij zowel atherosclerose als na een hartinfarct. Show less
Vitamin D plays an active role in the modulation of innate and adaptive immune responses as well as in the protection against respiratory pathogens, e.g. by increasing expression of the... Show moreVitamin D plays an active role in the modulation of innate and adaptive immune responses as well as in the protection against respiratory pathogens, e.g. by increasing expression of the antimicrobial peptide hCAP18/LL-37. The main aim of this thesis was to elucidate the role of inflammation on the protective effects of vitamin D on respiratory host defense responses in chronic inflammatory lung diseases such as chronic obstructive pulmonary disease (COPD). Airway epithelial host defense responses in COPD patients are defective and these patients are therefore more susceptible to respiratory infections. In this thesis we have shown that exposure to cigarette smoke, a main risk factor for COPD, reduced expression of certain host defense mediators by affecting end-stage airway epithelial differentiation and might explains why COPD patients are more susceptible to respiratory infections. We have further demonstrated in the studies presented in this thesis that certain airway inflammatory mediators could possibly interfere with vitamin D metabolism by promoting expression of vitamin D degrading enzyme CYP24A1, thereby reducing local levels of vitamin D and accompanying protective antimicrobial and anti-inflammatory actions. These new insights may yield possible new strategies to target CYP24A1 that enhance local levels and signaling of vitamin D to increase protection against exacerbations in COPD patients. Show less
Cardiometabolic diseases including atherosclerotic cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD) are the leading cause of preventable death worldwide.... Show moreCardiometabolic diseases including atherosclerotic cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD) are the leading cause of preventable death worldwide. Hypercholesterolemia and inflammation are common major risk factors for atherosclerotic CVD as well as NAFLD. The studies described in this thesis aimed to get insight in strategies how to further improve cholesterol metabolism and inflammation, by exploring the therapeutic potential of brown fat activation and transcription factors involved in both processes. The results described in this thesis have increased our insight into regulation of cholesterol metabolism and inflammation by brown fat and nuclear receptors, respectively, and provided promising leads for innovative treatment of cardiometabolic diseases including brown fat activation, Δ24-dehydrocholesterol reductase inhibition, and farnesoid X receptor activation. Show less
Cardiovascular disease is a major global burden and atherosclerosis is the main underlying pathological process. Despite better management of cholesterol levels, there remains a significant... Show moreCardiovascular disease is a major global burden and atherosclerosis is the main underlying pathological process. Despite better management of cholesterol levels, there remains a significant residual risk of developing atherosclerosis and cardiovascular events. Hence, novel pathways and targets should be identified to optimize atherosclerosis therapy. Despite dyslipidemia, the immune system is also heavily involved in the pathophysiology of atherosclerosis. Protective immune responses in the acute setting of increased cholesterol levels eventually turn into debilitating responses when the immune system is chronically stimulated. Hence, we aimed to identify new therapeutic targets to dampen the immune response in atherosclerosis. More specifically, we focused our efforts on modulating the B lymphocyte response, for which there was a scarcity of data. In this thesis we describe novel ways to modulate the B cell response in atherosclerosis. We have found that there are specific B cell subsets that have different effects on the progress of atherosclerosis. For instance, removal of TIM-1+ B cells resulted in increased atherosclerosis, while removal of BTLA+ follicular B cells reduced atherosclerosis. In conclusion, this thesis provides promising immunological targets for the treatment of atherosclerosis. Show less
The aim of this thesis is to shed light on the biological background of progression of sporadic vestibular schwannomas. The results of our studies indicate that, in different ways, intratumoral... Show moreThe aim of this thesis is to shed light on the biological background of progression of sporadic vestibular schwannomas. The results of our studies indicate that, in different ways, intratumoral inflammation seems to be important in the clinical progression of these tumors. By stimulating angiogenesis and through inhibition of antitumor immune responses tumor associated macrophages may allow some tumors to progress faster and reach a larger volume.M-CSF and IL-34 may play a regulatory role when it comes to macrophage activity within vestibular schwannomas, thereby potentially making them targets for therapy. These outcomes must be interpreted with caution. It is important to note that the results of the comparisons we made are observations of association. There is always the possibility that these findings are epiphenomena of a larger biological growth process and therefore not directly related to one another.In the search for new drugs capable of targeting tumor biological factors involved in the progression of vestibular schwannomas it is important to realize that our findings also indicate that these tumors may be protected by barrier proteins such as BCRP. Show less
Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease, is a rare genetic disorder, known for its endothelial dysplasia causing vessel malformations, severe nose bleeds and... Show moreHereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease, is a rare genetic disorder, known for its endothelial dysplasia causing vessel malformations, severe nose bleeds and internal bleedings. In the majority of patients mutations are found in genes belonging to the TGFβ superfamily, causing a disbalance in the TGFβ signaling pathway by haploinsufficiency of the remaining functional protein. In this thesis we studied different aims and approaches to influence HHT1-MNC homing and differentiation to restore their contribution to tissue repair. In various experimental methods inducing ischemic and/or direct tissue damage, we aimed to improve tissue repair in the Eng+/- mice. Using DPP4 inhibition, we increased the SDF1-CXCR4 homing mechanism, to restore the impaired homing capacity of the HHT1-MNCs. Furthermore, we focused on correcting the M1/M2 differentiation in Eng+/- mice. Via use of the BMP receptor inhibitor LDN we aimed to restore the skewed BMP/TGFβ signaling; stimulating the TGFβ pathway signaling to induce M2 differentiation. We concluded that DPP4 inhibition can be used to improve the HHT1 immune system and tissue repair, and is best used in concert with other drugs or therapies that stimulate cardiac or tissue repair, like anti-coagulants or cell therapy. Show less
Cardiovascular disease (CVD) is the collective term for diseases that involve the heart or circulation and CVDs are a major cause of mortality and morbidity worldwide. The aim of thesis was to... Show moreCardiovascular disease (CVD) is the collective term for diseases that involve the heart or circulation and CVDs are a major cause of mortality and morbidity worldwide. The aim of thesis was to investigate the role of inflammation in CVD related cardiac and vascular remodelling, which may lead to potential therapeutic agents. We investigated the therapeutic potential of antibodies directed against phosphorylcholine (PC), an endogenous ligand capable of triggering the innate immune system, which is expressed by apoptotic cells and oxidized LDL, in mouse models for myocardial infarction (MI). We found that treatment with anti-PC antibodies reduces adverse cardiac remodelling after both permanent MI as myocardial ischemia reperfusion (MI-R) injury. Furthermore, we found that treatment with annexin A5 also reduces adverse cardiac remodelling after MI-R injury. Interestingly, both anti-PC as annexin A5 treatment reduced the post MI inflammatory response. Next, we investigated the role of PCAF, an inflammatory related epigenetic factor, in vascular remodelling. We found that PCAF deficiency and treatment with a PCAF inhibitor reduces adverse vascular remodelling. Finally, we investigated the role of microRNAs, small RNA molecules that can affect expression of many different gene simultaneously, in vascular remodelling. We show that inhibition of microRNA-495 reduces adverse vascular remodelling. Show less
In this thesis we investigated various mechanisms by which the immune system plays a role in the development of diabetic nephropathy. In chapter 2 we describe that APOC1-tg mice develop... Show moreIn this thesis we investigated various mechanisms by which the immune system plays a role in the development of diabetic nephropathy. In chapter 2 we describe that APOC1-tg mice develop glomerulosclerosis at 15 months of age, with increased number of glomerular macrophages. Our results suggest that apoCI may exacerbate the development of DN by increasing the inflammatory response in activated glomerular macrophages. In chapter 3 we demonstrate that sFLT-1 significantly improves kidney function, resolves diabetes-related kidney damage, and reduces endothelial cell activation and inflammation, suggesting that sFLT-1 can reduce the severity of DN by reducing glomerular inflammation and supporting cellular repair mechanisms.In chapter 4 we show that reducing endoglin levels diminished VEGF-A-induced endothelial activation by increasing pAkt and reducing pATF-2. These data suggest that targeting endoglin may have therapeutic value in patients who are at risk for developing DN.In chapter 5 we demonstrate that renal complement activation is associated with more severe classes of DN, reduced kidney function, and the presence of histological lesions.In chapter 6 we describe that transfecting APOC1-tg mice with sFlt-1 does not accelerate development of glomerulosclerosis, but lowered the number of glomerular macrophages. These data suggest that sFLT-1 treatment has an anti-inflammatory effect. Show less
Cardiovascular diseases (CVD), which are mainly caused by the development of atherosclerosis, are the leading cause of morbidity and mortality in Western Society. Two main risk factors for the... Show moreCardiovascular diseases (CVD), which are mainly caused by the development of atherosclerosis, are the leading cause of morbidity and mortality in Western Society. Two main risk factors for the development of atherosclerosis are hyperlipidemia and inflammation, that cause accumulation of lipids and immune cells, respectively, in the arterial wall. While activation of brown adipose tissue (BAT) is a promising strategy to alleviate hyperlipidemia, reduction of inflammation is also thought to reduce atherosclerosis progression. In this thesis, we aimed to address two key objectives: 1) to identify genetic targets in mice and men that are involved in BAT activity and evaluate their effects on lipoprotein metabolism and atherosclerosis development, and 2) to identify genetic targets in mice that are involved in modulation of the immune system and evaluate their effects on atherosclerosis development. Chapter 1 serves as a general introduction in which hyperlipidemia and inflammation are introduced as the two main causes for atherosclerosis development. More specifically, firstly the physiology and role of BAT in lipoprotein metabolism and atherosclerosis development are explained. Secondly, the contribution of pro- and anti-inflammatory cytokines as well as specific receptors on immune cells in propelling immune responses are explained in the context of atherosclerosis development. Show less
Within this thesis, several diseases central in the field of cardiovascular disease will be outlined. First, the central dogma of molecular biology, RNA biology in general, RNA (alternative... Show moreWithin this thesis, several diseases central in the field of cardiovascular disease will be outlined. First, the central dogma of molecular biology, RNA biology in general, RNA (alternative)splicing and the role of RNA-binding proteins within these processes will be discussed to enhance the accessibility to non-molecular biologists. Subsequently, the current literature and insights into the RNA-binding protein Quaking will be outlined. Thereafter, a brief summary of the role of many distinct RNA-binding proteins (RBPs) in the cardiovascular system is provided, detailing their importance in the heart and cells of the blood vessels. This review provides some historical and biological perspectives, while simultaneously highlighting many recent advances in our understanding of RBP function in cardiovascular health and disease. By harnessing established and novel techniques, including RNA-sequencing, this thesis will describe the role of Quaking in vascular stenosis, atherosclerosis, inflammation and endothelial barrier function. Collectively, Quaking can be described as a genome-wide governor of RNA-processing that results in the proper translation into functional proteins. This thesis describes which RNA transcripts are under control of Quaking, which alternative transcripts are being generated through modulation by Quaking, while also describing the unique role for this protein in health and cardiovascular and renal disease. Show less
Immunometabolism focusses on the interplay between immunological and metabolic processes, both at a systemic and a cellular level. This thesis is divided into two parts based on these two... Show moreImmunometabolism focusses on the interplay between immunological and metabolic processes, both at a systemic and a cellular level. This thesis is divided into two parts based on these two levels. The first part focusses on the infrapatellar fat pad (IFP), an adipose tissue located in the knee, and the potential role in the pathophysiology of osteoarthritis. Therefore, we characterized the IFP based on a cellular and molecular level and found that the inflammatory state of the joint does affect the cellular load of the IFP, however, the secretory profile of the IFP does not seem to be affected. Furthermore, obesity-related changes normally found in adipose tissue were not present in the IFP. When characterizing the IFP we found two interesting cell populations, IL-6-secreting T cells and macrophages with an anti-inflammatory phenotype secreting pro-inflammatory cytokines. Both populations could be involved in the pathophysiology of the osteoarthritic joint. Furthermore, in the second part we focussed on cellular metabolism where we determined the mechanism by which fatty acids exert their effect on T cells. We found that fatty acids are not served as energy, however, whether it is used for daughter cells or influencing cell signalling remains to be elucidated. Show less