Lauran Stöger - Academia.edu (original) (raw)

Papers by Lauran Stöger

Radiology

T he ongoing coronavirus disease 2019 (COVID-19) pandemic, a disease caused by severe acute respi... more T he ongoing coronavirus disease 2019 (COVID-19) pandemic, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought about a need for timely and high diagnostic performance tests for detecting COVID-19. The reference standard for diagnosing COVID-19 is a SARS-CoV-2 real-time reverse-transcription polymerase chain reaction (RT-PCR) test of respiratory tract specimens. Unfortunately, RT-PCR has limited sensitivity, and clinical test performance is dependent on test sample quality, viral load kinetics, and duration of symptoms (1-5). Moreover, the time required for laboratory testing and reporting of RT-PCR results can be substantial, which is undesirable in crowded emergency departments. Hence, in hospitals there is a need for rapid and reliable diagnostics of COVID-19 for appropriate isolation in patient groups with high suspicion of disease. CT is widely available and offers

Journal of Cardiovascular Development and Disease

Background: Kommerell’s diverticulum is a rare vascular anomaly characterized as an outpouch at t... more Background: Kommerell’s diverticulum is a rare vascular anomaly characterized as an outpouch at the onset of an aberrant subclavian artery. In the variant of a right-sided aortic arch, the trachea and esophagus are enclosed dorsally by the arch. In the configuration of an aberrant left subclavian artery, a Kommerell’s diverticulum and persisting ductus arteriosus or ductal ligament enclose the lateral side, forming a vascular ring which may result in (symptomatic) esophageal or tracheal compression. Spontaneous rupture of an aneurysmatic Kommerell’s diverticulum has also been reported. Due to the rarity of this condition and underreporting in the literature, the clinical implications of a Kommerell’s diverticulum are not well defined. Case summary: We describe seven consecutive adult patients with a right-sided aortic arch and an aberrant course of the left subclavian artery (arteria lusoria), and a Kommerell’s diverticulum, diagnosed in our tertiary hospital. One patient had severe...

Radiology

CORADS-AI is a freely accessible deep learning algorithm that automatically assigns CO-RADS and C... more CORADS-AI is a freely accessible deep learning algorithm that automatically assigns CO-RADS and CT severity scores to non-contrast CT scans of patients suspected of COVID-19 with high diagnostic performance.

Radiology

CO-RADS, for COVID-19 Reporting and Data System, is a categorical assessment scheme for chest CT ... more CO-RADS, for COVID-19 Reporting and Data System, is a categorical assessment scheme for chest CT in patients suspected of COVID-19, representing the level of suspicion for pulmonary involvement. The substantial agreement among observers and its discriminatory value make it well-suited for use in clinical practice. Key results • CO-RADS, for COVID-19 Reporting and Data System, provides a standardized assessment scheme that simplifies reporting with a five-point scale of suspicion for pulmonary involvement of COVID-19 on chest CT • CO-RADS has a moderate to substantial agreement among observers with an overall Fleiss' kappa of 0.47 (95% CI 0.45-0.49). • The discriminatory power of CO-RADS for diagnosing COVID-19 was high, with a mean area under the ROC curve of 0.91 (95% CI 0.85-0.97) for positive RT-PCR results. Abbreviations RT-PCR: reverse transcriptase-polymerase chain reaction. ROC: receiver operating characteristics.

Current Opinion in Pulmonary Medicine, 2016

Thrombosis and haemostasis, Aug 30, 2016

Inflammatory responses and cholesterol homeostasis are interconnected in atherogenesis. Interleuk... more Inflammatory responses and cholesterol homeostasis are interconnected in atherogenesis. Interleukin (IL)-10 is an important anti-inflammatory cytokine, known to suppress atherosclerosis development. However, the specific cell types responsible for the atheroprotective effects of IL-10 remain to be defined and knowledge on the actions of IL-10 in cholesterol homeostasis is scarce. Here we investigated the functional involvement of myeloid IL-10-mediated atheroprotection. To do so, bone marrow from IL-10 receptor 1 (IL-10R1) wild-type and myeloid IL-10R1-deficient mice was transplanted to lethally irradiated female LDLR-/- mice. Hereafter, mice were given a high cholesterol diet for 10 weeks after which atherosclerosis development and cholesterol metabolism were investigated. In vitro, myeloid IL-10R1 deficiency resulted in a pro-inflammatory macrophage phenotype. However, in vivo significantly reduced lesion size and severity was observed. This phenotype was associated with lower mye...

Current Atherosclerosis Reports, 2012

Recent years have seen a tremendous development of our insight into the biology of atherosclerosi... more Recent years have seen a tremendous development of our insight into the biology of atherosclerosis and its acute thrombotic manifestations. Inflammation now takes center stage among traditional risk factors as a decisive factor in cardiovascular risk. Consequently, its assessment and modulation have become key to clinical care and fundamental research alike. Plaque macrophages orchestrate many of the inflammatory processes that occur throughout atherogenesis. These cells are characteristically heterogeneous and adopt diverse activation states in response to micro-environmental triggers. In this review, macrophagemediated inflammation in atherosclerosis sets the scene for a discussion of the gene regulatory mechanisms that facilitate and shape polarized macrophage phenotypes. When applicable, we consider these factors within the context of atherosclerosis and reflect on opportunities for future application.

The FASEB Journal, 2014

Atherosclerosis is a lipid-driven inflammatory disease of the vessel wall, characterized by the c... more Atherosclerosis is a lipid-driven inflammatory disease of the vessel wall, characterized by the chronic activation of macrophages. We investigated whether the helminth-derived antigens [soluble egg antigens (SEAs)] could modulate macrophage inflammatory responses and protect against atherosclerosis in mice. In bone marrow-derived macrophages, SEAs induce anti-inflammatory macrophages, typified by high levels of IL-10 and reduced secretion of proinflammatory mediators. In hyperlipidemic LDLR ؊/؊ mice, SEA treatment reduced plaque size by 44%, and plaques were less advanced compared with PBS-injected littermate controls. The atheroprotective effect of SEAs was found to be mainly independent of cholesterol lowering and T-lymphocyte responses but instead could be attributed to diminished myeloid cell activation. SEAs reduced circulating neutrophils and inflammatory Ly6C high monocytes, and macrophages showed high IL-10 production. In line with the observed systemic effects, atherosclerotic lesions of SEA-treated mice showed reduced intraplaque inflammation as inflammatory markers [TNF-␣, monocyte chemotactic protein 1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and CD68], neutrophil content, and newly recruited macro-phages were decreased. We show that SEA treatment protects against atherosclerosis development by dampening inflammatory responses. In the future, helminthderived components may provide novel opportunities to treat chronic inflammatory diseases, as they diminish systemic inflammation and reduce the activation of immune cells.

PLoS ONE, 2012

microRNA-155 (miR155) is a central regulator of immune responses that is induced by inflammatory ... more microRNA-155 (miR155) is a central regulator of immune responses that is induced by inflammatory mediators. Although miR155 is considered to be a pro-inflammatory microRNA, in vitro reports show anti-inflammatory effects in lipid-loaded cells. In this study we examined the role of miR155 in atherosclerosis in vivo using bone marrow transplantation from miR155 deficient or wildtype mice to hyperlipidemic mice. Hematopoietic deficiency of miR155 enhanced atherosclerotic plaque development and decreased plaque stability, as evidenced by increased myeloid inflammatory cell recruitment to the plaque. The increased inflammatory state was mirrored by a decrease in circulating CD4 + CD25 + FoxP3 + regulatory T cells, and an increase in granulocytes (CD11b + Ly6G +) in blood of miR155 2/2 transplanted mice. Moreover, we show for the first time a crucial role of miR155 in monocyte subset differentiation, since hematopoietic deficiency of miR155 increases the 'inflammatory' monocyte subset (CD11b + Ly6G 2 Ly6C hi) and reduces 'resident' monocytes (CD11b + Ly6G 2 Ly6C low) in the circulation. Furthermore, cytokine production by resident peritoneal macrophages of miR155 2/2 transplanted hyperlipidemic mice was skewed towards a more pro-inflammatory state since anti-inflammatory IL-10 production was reduced. In conclusion, in this hyperlipidemic mouse model miR155 acts as an anti-inflammatory, atheroprotective microRNA. Additionally, besides a known role in lymphoid cell development, we show a crucial role of miR155 in myeloid lineage differentiation.

Current Vascular Pharmacology, 2010

Atherosclerosis is a chronic inflammatory disease involving many cell types with a well-accepted ... more Atherosclerosis is a chronic inflammatory disease involving many cell types with a well-accepted key role for macrophages. A wide array of different properties and functional characteristics are attributed to macrophages present in the atherosclerotic plaque. As an increasing body of evidence strengthens the consensus that macrophages comprise a heterogeneous population, several co-existing subtypes with diverse, even opposing specialties have already been described in fields like parasitology, tumour biology and metabolic disorders. However, macrophage heterogeneity within atherosclerotic lesions has not been studied in detail yet. In this review we will introduce the characteristics of macrophage subsets in other pathologies and address the presence and possible roles of distinct macrophage subtypes in the rapidly evolving field of atherosclerosis. Finally, we make an effort to relate these subtypes to disease progression and explore a number of opportunities for novel diagnostic and therapeutic approaches.

Circulation, 2013

C ardiac hypertrophy and consequent heart failure in response to chronic hypertension represent o... more C ardiac hypertrophy and consequent heart failure in response to chronic hypertension represent one of the major health challenges in Western societies. 1 Over the past decade, growing evidence has indicated the causative contribution of the immune system in hypertrophy and heart failure. 2-4 Angiotensin II (AngII), one of the major mediators of Background-Cardiac hypertrophy and subsequent heart failure triggered by chronic hypertension represent major challenges for cardiovascular research. Beyond neurohormonal and myocyte signaling pathways, growing evidence suggests inflammatory signaling pathways as therapeutically targetable contributors to this process. We recently reported that microRNA-155 is a key mediator of cardiac inflammation and injury in infectious myocarditis. Here, we investigated the impact of microRNA-155 manipulation in hypertensive heart disease. Methods and Results-Genetic loss or pharmacological inhibition of the leukocyte-expressed microRNA-155 in mice markedly reduced cardiac inflammation, hypertrophy, and dysfunction on pressure overload. These alterations were macrophage dependent because in vivo cardiomyocyte-specific microRNA-155 manipulation did not affect cardiac hypertrophy or dysfunction, whereas bone marrow transplantation from wild-type mice into microRNA-155 knockout animals rescued the hypertrophic response of the cardiomyocytes and vice versa. In vitro, media from microRNA-155 knockout macrophages blocked the hypertrophic growth of stimulated cardiomyocytes, confirming that macrophages influence myocyte growth in a microRNA-155-dependent paracrine manner. These effects were at least partly mediated by the direct microRNA-155 target suppressor of cytokine signaling 1 (Socs1) because Socs1 knockdown in microRNA-155 knockout macrophages largely restored their hypertrophy-stimulating potency. Conclusions-Our findings reveal that microRNA-155 expression in macrophages promotes cardiac inflammation, hypertrophy, and failure in response to pressure overload. These data support the causative significance of inflammatory signaling in hypertrophic heart disease and demonstrate the feasibility of therapeutic microRNA targeting of inflammation in heart failure.

Atherosclerosis

Objective Macrophages are decisive in the chronic inflammatory processes that drive atherogenesis... more Objective Macrophages are decisive in the chronic inflammatory processes that drive atherogenesis. The purpose of this study was to explore the presence and spatial distribution of polarized macrophage populations in human atherosclerosis. Methods & results We used transcriptomics and immunohistochemistry to analyze macrophage subset dynamics in successive stages of atherogenesis. Developing lesions progressively accumulated both M1 and M2 cells, as was signified by the enhanced expression of associated markers at the transcriptional and protein level. Histologically, these markers were confined to overlapping, but spatially distinct CD68+ areas of the intima. We subsequently quantified the presence of these markers in relation to morphological determinants of plaque stability. In line with their pro-inflammatory characteristics, M1 macrophages dominated the rupture-prone shoulder regions of the plaque over M2 polarized cells, while the fibrous caps of lesions showed no significant ...

EMBO molecular medicine, 2014

Macrophages are key immune cells found in atherosclerotic plaques and critically shape atheroscle... more Macrophages are key immune cells found in atherosclerotic plaques and critically shape atherosclerotic disease development. Targeting the functional repertoire of macrophages may hold novel approaches for future atherosclerosis management. Here, we describe a previously unrecognized role of the epigenomic enzyme Histone deacetylase 3 (Hdac3) in regulating the atherosclerotic phenotype of macrophages. Using conditional knockout mice, we found that myeloid Hdac3 deficiency promotes collagen deposition in atherosclerotic lesions and thus induces a stable plaque phenotype. Also, macrophages presented a switch to anti-inflammatory wound healing characteristics and showed improved lipid handling. The pro-fibrotic phenotype was directly linked to epigenetic regulation of the Tgfb1 locus upon Hdac3 deletion, driving smooth muscle cells to increased collagen production. Moreover, in humans, HDAC3 was the sole Hdac upregulated in ruptured atherosclerotic lesions, Hdac3 associated with inflamm...

Radiology

T he ongoing coronavirus disease 2019 (COVID-19) pandemic, a disease caused by severe acute respi... more T he ongoing coronavirus disease 2019 (COVID-19) pandemic, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought about a need for timely and high diagnostic performance tests for detecting COVID-19. The reference standard for diagnosing COVID-19 is a SARS-CoV-2 real-time reverse-transcription polymerase chain reaction (RT-PCR) test of respiratory tract specimens. Unfortunately, RT-PCR has limited sensitivity, and clinical test performance is dependent on test sample quality, viral load kinetics, and duration of symptoms (1-5). Moreover, the time required for laboratory testing and reporting of RT-PCR results can be substantial, which is undesirable in crowded emergency departments. Hence, in hospitals there is a need for rapid and reliable diagnostics of COVID-19 for appropriate isolation in patient groups with high suspicion of disease. CT is widely available and offers

Journal of Cardiovascular Development and Disease

Background: Kommerell’s diverticulum is a rare vascular anomaly characterized as an outpouch at t... more Background: Kommerell’s diverticulum is a rare vascular anomaly characterized as an outpouch at the onset of an aberrant subclavian artery. In the variant of a right-sided aortic arch, the trachea and esophagus are enclosed dorsally by the arch. In the configuration of an aberrant left subclavian artery, a Kommerell’s diverticulum and persisting ductus arteriosus or ductal ligament enclose the lateral side, forming a vascular ring which may result in (symptomatic) esophageal or tracheal compression. Spontaneous rupture of an aneurysmatic Kommerell’s diverticulum has also been reported. Due to the rarity of this condition and underreporting in the literature, the clinical implications of a Kommerell’s diverticulum are not well defined. Case summary: We describe seven consecutive adult patients with a right-sided aortic arch and an aberrant course of the left subclavian artery (arteria lusoria), and a Kommerell’s diverticulum, diagnosed in our tertiary hospital. One patient had severe...

Radiology

CORADS-AI is a freely accessible deep learning algorithm that automatically assigns CO-RADS and C... more CORADS-AI is a freely accessible deep learning algorithm that automatically assigns CO-RADS and CT severity scores to non-contrast CT scans of patients suspected of COVID-19 with high diagnostic performance.

Radiology

CO-RADS, for COVID-19 Reporting and Data System, is a categorical assessment scheme for chest CT ... more CO-RADS, for COVID-19 Reporting and Data System, is a categorical assessment scheme for chest CT in patients suspected of COVID-19, representing the level of suspicion for pulmonary involvement. The substantial agreement among observers and its discriminatory value make it well-suited for use in clinical practice. Key results • CO-RADS, for COVID-19 Reporting and Data System, provides a standardized assessment scheme that simplifies reporting with a five-point scale of suspicion for pulmonary involvement of COVID-19 on chest CT • CO-RADS has a moderate to substantial agreement among observers with an overall Fleiss' kappa of 0.47 (95% CI 0.45-0.49). • The discriminatory power of CO-RADS for diagnosing COVID-19 was high, with a mean area under the ROC curve of 0.91 (95% CI 0.85-0.97) for positive RT-PCR results. Abbreviations RT-PCR: reverse transcriptase-polymerase chain reaction. ROC: receiver operating characteristics.

Current Opinion in Pulmonary Medicine, 2016

Thrombosis and haemostasis, Aug 30, 2016

Inflammatory responses and cholesterol homeostasis are interconnected in atherogenesis. Interleuk... more Inflammatory responses and cholesterol homeostasis are interconnected in atherogenesis. Interleukin (IL)-10 is an important anti-inflammatory cytokine, known to suppress atherosclerosis development. However, the specific cell types responsible for the atheroprotective effects of IL-10 remain to be defined and knowledge on the actions of IL-10 in cholesterol homeostasis is scarce. Here we investigated the functional involvement of myeloid IL-10-mediated atheroprotection. To do so, bone marrow from IL-10 receptor 1 (IL-10R1) wild-type and myeloid IL-10R1-deficient mice was transplanted to lethally irradiated female LDLR-/- mice. Hereafter, mice were given a high cholesterol diet for 10 weeks after which atherosclerosis development and cholesterol metabolism were investigated. In vitro, myeloid IL-10R1 deficiency resulted in a pro-inflammatory macrophage phenotype. However, in vivo significantly reduced lesion size and severity was observed. This phenotype was associated with lower mye...

Current Atherosclerosis Reports, 2012

Recent years have seen a tremendous development of our insight into the biology of atherosclerosi... more Recent years have seen a tremendous development of our insight into the biology of atherosclerosis and its acute thrombotic manifestations. Inflammation now takes center stage among traditional risk factors as a decisive factor in cardiovascular risk. Consequently, its assessment and modulation have become key to clinical care and fundamental research alike. Plaque macrophages orchestrate many of the inflammatory processes that occur throughout atherogenesis. These cells are characteristically heterogeneous and adopt diverse activation states in response to micro-environmental triggers. In this review, macrophagemediated inflammation in atherosclerosis sets the scene for a discussion of the gene regulatory mechanisms that facilitate and shape polarized macrophage phenotypes. When applicable, we consider these factors within the context of atherosclerosis and reflect on opportunities for future application.

The FASEB Journal, 2014

Atherosclerosis is a lipid-driven inflammatory disease of the vessel wall, characterized by the c... more Atherosclerosis is a lipid-driven inflammatory disease of the vessel wall, characterized by the chronic activation of macrophages. We investigated whether the helminth-derived antigens [soluble egg antigens (SEAs)] could modulate macrophage inflammatory responses and protect against atherosclerosis in mice. In bone marrow-derived macrophages, SEAs induce anti-inflammatory macrophages, typified by high levels of IL-10 and reduced secretion of proinflammatory mediators. In hyperlipidemic LDLR ؊/؊ mice, SEA treatment reduced plaque size by 44%, and plaques were less advanced compared with PBS-injected littermate controls. The atheroprotective effect of SEAs was found to be mainly independent of cholesterol lowering and T-lymphocyte responses but instead could be attributed to diminished myeloid cell activation. SEAs reduced circulating neutrophils and inflammatory Ly6C high monocytes, and macrophages showed high IL-10 production. In line with the observed systemic effects, atherosclerotic lesions of SEA-treated mice showed reduced intraplaque inflammation as inflammatory markers [TNF-␣, monocyte chemotactic protein 1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and CD68], neutrophil content, and newly recruited macro-phages were decreased. We show that SEA treatment protects against atherosclerosis development by dampening inflammatory responses. In the future, helminthderived components may provide novel opportunities to treat chronic inflammatory diseases, as they diminish systemic inflammation and reduce the activation of immune cells.

PLoS ONE, 2012

microRNA-155 (miR155) is a central regulator of immune responses that is induced by inflammatory ... more microRNA-155 (miR155) is a central regulator of immune responses that is induced by inflammatory mediators. Although miR155 is considered to be a pro-inflammatory microRNA, in vitro reports show anti-inflammatory effects in lipid-loaded cells. In this study we examined the role of miR155 in atherosclerosis in vivo using bone marrow transplantation from miR155 deficient or wildtype mice to hyperlipidemic mice. Hematopoietic deficiency of miR155 enhanced atherosclerotic plaque development and decreased plaque stability, as evidenced by increased myeloid inflammatory cell recruitment to the plaque. The increased inflammatory state was mirrored by a decrease in circulating CD4 + CD25 + FoxP3 + regulatory T cells, and an increase in granulocytes (CD11b + Ly6G +) in blood of miR155 2/2 transplanted mice. Moreover, we show for the first time a crucial role of miR155 in monocyte subset differentiation, since hematopoietic deficiency of miR155 increases the 'inflammatory' monocyte subset (CD11b + Ly6G 2 Ly6C hi) and reduces 'resident' monocytes (CD11b + Ly6G 2 Ly6C low) in the circulation. Furthermore, cytokine production by resident peritoneal macrophages of miR155 2/2 transplanted hyperlipidemic mice was skewed towards a more pro-inflammatory state since anti-inflammatory IL-10 production was reduced. In conclusion, in this hyperlipidemic mouse model miR155 acts as an anti-inflammatory, atheroprotective microRNA. Additionally, besides a known role in lymphoid cell development, we show a crucial role of miR155 in myeloid lineage differentiation.

Current Vascular Pharmacology, 2010

Atherosclerosis is a chronic inflammatory disease involving many cell types with a well-accepted ... more Atherosclerosis is a chronic inflammatory disease involving many cell types with a well-accepted key role for macrophages. A wide array of different properties and functional characteristics are attributed to macrophages present in the atherosclerotic plaque. As an increasing body of evidence strengthens the consensus that macrophages comprise a heterogeneous population, several co-existing subtypes with diverse, even opposing specialties have already been described in fields like parasitology, tumour biology and metabolic disorders. However, macrophage heterogeneity within atherosclerotic lesions has not been studied in detail yet. In this review we will introduce the characteristics of macrophage subsets in other pathologies and address the presence and possible roles of distinct macrophage subtypes in the rapidly evolving field of atherosclerosis. Finally, we make an effort to relate these subtypes to disease progression and explore a number of opportunities for novel diagnostic and therapeutic approaches.

Circulation, 2013

C ardiac hypertrophy and consequent heart failure in response to chronic hypertension represent o... more C ardiac hypertrophy and consequent heart failure in response to chronic hypertension represent one of the major health challenges in Western societies. 1 Over the past decade, growing evidence has indicated the causative contribution of the immune system in hypertrophy and heart failure. 2-4 Angiotensin II (AngII), one of the major mediators of Background-Cardiac hypertrophy and subsequent heart failure triggered by chronic hypertension represent major challenges for cardiovascular research. Beyond neurohormonal and myocyte signaling pathways, growing evidence suggests inflammatory signaling pathways as therapeutically targetable contributors to this process. We recently reported that microRNA-155 is a key mediator of cardiac inflammation and injury in infectious myocarditis. Here, we investigated the impact of microRNA-155 manipulation in hypertensive heart disease. Methods and Results-Genetic loss or pharmacological inhibition of the leukocyte-expressed microRNA-155 in mice markedly reduced cardiac inflammation, hypertrophy, and dysfunction on pressure overload. These alterations were macrophage dependent because in vivo cardiomyocyte-specific microRNA-155 manipulation did not affect cardiac hypertrophy or dysfunction, whereas bone marrow transplantation from wild-type mice into microRNA-155 knockout animals rescued the hypertrophic response of the cardiomyocytes and vice versa. In vitro, media from microRNA-155 knockout macrophages blocked the hypertrophic growth of stimulated cardiomyocytes, confirming that macrophages influence myocyte growth in a microRNA-155-dependent paracrine manner. These effects were at least partly mediated by the direct microRNA-155 target suppressor of cytokine signaling 1 (Socs1) because Socs1 knockdown in microRNA-155 knockout macrophages largely restored their hypertrophy-stimulating potency. Conclusions-Our findings reveal that microRNA-155 expression in macrophages promotes cardiac inflammation, hypertrophy, and failure in response to pressure overload. These data support the causative significance of inflammatory signaling in hypertrophic heart disease and demonstrate the feasibility of therapeutic microRNA targeting of inflammation in heart failure.

Atherosclerosis

Objective Macrophages are decisive in the chronic inflammatory processes that drive atherogenesis... more Objective Macrophages are decisive in the chronic inflammatory processes that drive atherogenesis. The purpose of this study was to explore the presence and spatial distribution of polarized macrophage populations in human atherosclerosis. Methods & results We used transcriptomics and immunohistochemistry to analyze macrophage subset dynamics in successive stages of atherogenesis. Developing lesions progressively accumulated both M1 and M2 cells, as was signified by the enhanced expression of associated markers at the transcriptional and protein level. Histologically, these markers were confined to overlapping, but spatially distinct CD68+ areas of the intima. We subsequently quantified the presence of these markers in relation to morphological determinants of plaque stability. In line with their pro-inflammatory characteristics, M1 macrophages dominated the rupture-prone shoulder regions of the plaque over M2 polarized cells, while the fibrous caps of lesions showed no significant ...

EMBO molecular medicine, 2014

Macrophages are key immune cells found in atherosclerotic plaques and critically shape atheroscle... more Macrophages are key immune cells found in atherosclerotic plaques and critically shape atherosclerotic disease development. Targeting the functional repertoire of macrophages may hold novel approaches for future atherosclerosis management. Here, we describe a previously unrecognized role of the epigenomic enzyme Histone deacetylase 3 (Hdac3) in regulating the atherosclerotic phenotype of macrophages. Using conditional knockout mice, we found that myeloid Hdac3 deficiency promotes collagen deposition in atherosclerotic lesions and thus induces a stable plaque phenotype. Also, macrophages presented a switch to anti-inflammatory wound healing characteristics and showed improved lipid handling. The pro-fibrotic phenotype was directly linked to epigenetic regulation of the Tgfb1 locus upon Hdac3 deletion, driving smooth muscle cells to increased collagen production. Moreover, in humans, HDAC3 was the sole Hdac upregulated in ruptured atherosclerotic lesions, Hdac3 associated with inflamm...