The immunometabolic role of indoleamine 2,3-dioxygenase in atherosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery wall. Ketelhuth Daniel F J Cardiovascular research Coronary heart disease and stroke, the two most common cardiovascular diseases worldwide, are triggered by complications of atherosclerosis. Atherosclerotic plaques are initiated by a maladaptive immune response triggered by accumulation of lipids in the artery wall. Hence, disease is influenced by several non-modifiable and modifiable risk factors, including dyslipidaemia, hypertension, smoking, and diabetes. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway of tryptophan (Trp) degradation, is modulated by inflammation and regarded as a key molecule driving immunotolerance and immunosuppressive mechanisms. A large body of evidence indicates that IDO-mediated Trp metabolism is involved directly or indirectly in atherogenesis. This review summarizes evidence from basic and clinical research showing that IDO is a major regulatory enzyme involved in the maintenance of immunohomeostasis in the vascular wall, as well as current knowledge about promising targets for the development of new anti-atherosclerotic drugs. 10.1093/cvr/cvz067
    Transcriptional control of inflammatory responses. Smale Stephen T,Natoli Gioacchino Cold Spring Harbor perspectives in biology The inflammatory response requires the activation of a complex transcriptional program that is both cell-type- and stimulus-specific and involves the dynamic regulation of hundreds of genes. In the context of an inflamed tissue, extensive changes in gene expression occur in both parenchymal cells and infiltrating cells of the immune system. Recently, basic transcriptional mechanisms that control inflammation have been clarified at a genome scale, particularly in macrophages and conventional dendritic cells. The regulatory logic of distinct groups of inflammatory genes can be explained to some extent by identifiable sequence-encoded features of their chromatin organization, which impact on transcription factor (TF) accessibility and impose different requirements for gene activation. Moreover, it has become apparent that the interplay between TFs activated by inflammatory stimuli and master regulators exerts a crucial role in controlling cell-type-specific transcriptional outputs. 10.1101/cshperspect.a016261
    Hypoxia and the regulation of myeloid cell metabolic imprinting: consequences for the inflammatory response. Sadiku Pranvera,Walmsley Sarah R EMBO reports Inflamed and infected tissue sites are characterised by oxygen and nutrient deprivation. The cellular adaptations to insufficient oxygenation, hypoxia, are mainly regulated by a family of transcription factors known as hypoxia-inducible factors (HIFs). The protein members of the HIF signalling pathway are critical regulators of both the innate and adaptive immune responses, and there is an increasing body of evidence to suggest that the elicited changes occur through cellular metabolic reprogramming. Here, we review the literature on innate immunometabolism to date and discuss the role of hypoxia in innate cell metabolic reprogramming, and how this determines immune responses. 10.15252/embr.201847388
    Endoplasmic reticulum stress in immunity. Bettigole Sarah E,Glimcher Laurie H Annual review of immunology Immune responses occur in the midst of a variety of cellular stresses that can severely perturb endoplasmic reticulum (ER) function. The unfolded protein response is a three-pronged signaling axis dedicated to preserving ER homeostasis. In this review, we highlight many important and emerging functional roles for ER stress in immunity, focusing on how the bidirectional cross talk between immunological processes and basic cell biology leads to pleiotropic signaling outcomes and enhanced sensitivity to inflammatory stimuli. We also discuss how dysregulated ER stress responses can provoke many diseases, including autoimmunity, firmly positioning the unfolded protein response as a major therapeutic target in human disease. 10.1146/annurev-immunol-032414-112116
    Immunotherapy for cardiovascular disease. Lutgens Esther,Atzler Dorothee,Döring Yvonne,Duchene Johan,Steffens Sabine,Weber Christian European heart journal The outcomes of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial have unequivocally proven that inflammation is a key driver of atherosclerosis and that targeting inflammation, in this case by using an anti-interleukin-1β antibody, improves cardiovascular disease (CVD) outcomes. This is especially true for CVD patients with a pro-inflammatory constitution. Although CANTOS has epitomized the importance of targeting inflammation in atherosclerosis, treatment with canakinumab did not improve CVD mortality, and caused an increase in infections. Therefore, the identification of novel drug targets and development of novel therapeutics that block atherosclerosis-specific inflammatory pathways and exhibit limited immune-suppressive side effects, as pursued in our collaborative research centre, are required to optimize immunotherapy for CVD. In this review, we will highlight the potential of novel immunotherapeutic targets that are currently considered to become a future treatment for CVD. 10.1093/eurheartj/ehz283
    Regulation of macrophage immunometabolism in atherosclerosis. Koelwyn Graeme J,Corr Emma M,Erbay Ebru,Moore Kathryn J Nature immunology After activation, cells of the myeloid lineage undergo robust metabolic transitions, as well as discrete epigenetic changes, that can dictate both ongoing and future inflammatory responses. In atherosclerosis, in which macrophages play central roles in the initiation, growth, and ultimately rupture of arterial plaques, altered metabolism is a key feature that dictates macrophage function and subsequent disease progression. This Review explores how factors central to the plaque microenvironment (for example, altered cholesterol metabolism, oxidative stress, hypoxia, apoptotic and necrotic cells, and hyperglycemia) shape the metabolic rewiring of macrophages in atherosclerosis as well as how these metabolic shifts in turn alter macrophage immune-effector and tissue-reparative functions. Finally, this overview offers insight into the challenges and opportunities of harnessing metabolism to modulate aberrant macrophage responses in disease. 10.1038/s41590-018-0113-3
    The immunology of atherosclerosis. Gisterå Anton,Hansson Göran K Nature reviews. Nephrology Cardiovascular disease is the leading cause of death worldwide, both in the general population and among patients with chronic kidney disease (CKD). In most cases, the underlying cause of the cardiovascular event is atherosclerosis - a chronic inflammatory disease. CKD accelerates atherosclerosis via augmentation of inflammation, perturbation of lipid metabolism, and other mechanisms. In the artery wall, subendothelial retention of plasma lipoproteins triggers monocyte-derived macrophages and T helper type 1 (T1) cells to form atherosclerotic plaques. Inflammation is initiated by innate immune reactions to modified lipoproteins and is perpetuated by T1 cells that react to autoantigens from the apolipoprotein B100 protein of LDL. Other T cells are also active in atherosclerotic lesions; regulatory T cells inhibit pathological inflammation, whereas T17 cells can promote plaque fibrosis. The slow build-up of atherosclerotic plaques is asymptomatic, but plaque rupture or endothelial erosion can induce thrombus formation, leading to myocardial infarction or ischaemic stroke. Targeting risk factors for atherosclerosis has reduced mortality, but a need exists for novel therapies to stabilize plaques and to treat arterial inflammation. Patients with CKD would likely benefit from such preventive measures. 10.1038/nrneph.2017.51
    The non-canonical NF-κB pathway in immunity and inflammation. Sun Shao-Cong Nature reviews. Immunology The nuclear factor-κB (NF-κB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions. Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions. Defects in non-canonical NF-κB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases. Here we review the signalling mechanisms and the biological function of the non-canonical NF-κB pathway. We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-κB pathway activation, which may provide new opportunities for therapeutic strategies. 10.1038/nri.2017.52
    Inflammation, Immunity, and Infection in Atherothrombosis: JACC Review Topic of the Week. Libby Peter,Loscalzo Joseph,Ridker Paul M,Farkouh Michael E,Hsue Priscilla Y,Fuster Valentin,Hasan Ahmed A,Amar Salomon Journal of the American College of Cardiology Observations on human and experimental atherosclerosis, biomarker studies, and now a large-scale clinical trial support the operation of immune and inflammatory pathways in this disease. The factors that incite innate and adaptive immune responses implicated in atherogenesis and in lesion complication include traditional risk factors such as protein and lipid components of native and modified low-density lipoprotein, angiotensin II, smoking, visceral adipose tissue, and dysmetabolism. Infectious processes and products of the endogenous microbiome might also modulate atherosclerosis and its complications either directly, or indirectly by eliciting local and systemic responses that potentiate disease expression. Trials with antibiotics have not reduced recurrent cardiovascular events, nor have vaccination strategies yet achieved clinical translation. However, anti-inflammatory interventions such as anticytokine therapy and colchicine have begun to show efficacy in this regard. Thus, inflammatory and immune mechanisms can link traditional and emerging risk factors to atherosclerosis, and offer novel avenues for therapeutic intervention. 10.1016/j.jacc.2018.08.1043
    Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation. Garn Holger,Bahn Sabine,Baune Bernhard T,Binder Elisabeth B,Bisgaard Hans,Chatila Talal A,Chavakis Triantafyllos,Culmsee Carsten,Dannlowski Udo,Gay Steffen,Gern James,Haahtela Tari,Kircher Tilo,Müller-Ladner Ulf,Neurath Markus F,Preissner Klaus T,Reinhardt Christoph,Rook Graham,Russell Shannon,Schmeck Bernd,Stappenbeck Thaddeus,Steinhoff Ulrich,van Os Jim,Weiss Scott,Zemlin Michael,Renz Harald The Journal of allergy and clinical immunology Recent research indicates that chronic inflammatory diseases, including allergies and autoimmune and neuropsychiatric diseases, share common pathways of cellular and molecular dysregulation. It was the aim of the International von-Behring-Röntgen Symposium (October 16-18, 2014, in Marburg, Germany) to discuss recent developments in this field. These include a concept of biodiversity; the contribution of urbanization, lifestyle factors, and nutrition (eg, vitamin D); and new mechanisms of metabolic and immune dysregulation, such as extracellular and intracellular RNAs and cellular and mitochondrial stress. Epigenetic mechanisms contribute further to altered gene expression and therefore to the development of chronic inflammation. These novel findings provide the foundation for further development of preventive and therapeutic strategies. 10.1016/j.jaci.2016.02.046
    Targeting the Immune System in Atherosclerosis: JACC State-of-the-Art Review. Zhao Tian X,Mallat Ziad Journal of the American College of Cardiology Atherosclerosis has long been known as an inflammatory disease. However, whether targeting inflammation improves outcomes was unproven until the recent results of CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study). In this review, we reflect on why it has taken a long time to prove the inflammatory hypothesis of atherosclerosis and derive important lessons for the future. In particular, we discuss the off-target immune-modulatory effects of approved cardiovascular therapies, review the attempted anti-inflammatory therapies including the recently published CIRT (Cardiovascular Inflammation Reduction Trial), and discuss the likely reasons for their failures. We further build on CANTOS to review the immune-modulatory therapies for atherosclerosis currently in trials, and discuss the likelihood of their added value as well as the potential hazard associated with their use. We finally argue for a critical approach to the use of animal models, coupled with the use of humans as model organisms to accelerate the identification of the most appropriate targets. 10.1016/j.jacc.2018.12.083
    Anti-inflammatory therapies for atherosclerosis. Bäck Magnus,Hansson Göran K Nature reviews. Cardiology The view of atherosclerosis as an inflammatory disease has emerged from observations of immune activation and inflammatory signalling in human atherosclerotic lesions, from the definition of inflammatory biomarkers as independent risk factors for cardiovascular events, and from evidence of low-density lipoprotein-induced immune activation. Studies in animal models of hyperlipidaemia have also supported the beneficial effects of countering inflammation to delay atherosclerosis progression. Specific inflammatory pathways with relevance to human diseases have been identified, and inhibitors of these pathways are either already in use for the treatment of other diseases, or are under development and evaluation. These include 'classic' drugs (such as allopurinol, colchicine, and methotrexate), biologic therapies (for example tumour necrosis factor inhibitors and IL-1 neutralization), as well as targeting of lipid mediators (such as phospholipase inhibitors and antileukotrienes) or intracellular pathways (inhibition of NADPH oxidase, p38 mitogen-activated protein kinase, or phosphodiesterase). The evidence supporting the use of anti-inflammatory therapies for atherosclerosis is mainly based on either observational or small interventional studies evaluating surrogate markers of disease activity. Nevertheless, these data are crucial to understand the role of inflammation in atherosclerosis, and to design randomized controlled studies to evaluate the effect of specific anti-inflammatory strategies on cardiovascular outcomes. 10.1038/nrcardio.2015.5
    Inflammatory risk factors, biomarkers and associated therapy in ischaemic stroke. Esenwa Charles C,Elkind Mitchell S Nature reviews. Neurology Proinflammatory conditions, including acute and chronic infections, have been associated with an increased risk of stroke. The risk of stroke is increased by both the acute and chronic phases of a wide spectrum of proinflammatory conditions, suggesting that the association is related to activation of the inflammatory response rather than the condition itself. Different inflammatory mechanisms probably influence the risk of different stroke subtypes. This hypothesis is supported by observations that high levels of various immune system markers and acute phase reactants in otherwise healthy individuals have also been associated with ischaemic stroke subtypes. C-reactive protein, IL-6 and lipoprotein-associated phospholipase A2 are some of the inflammatory markers that have been associated with stroke risk and prognosis. Multiple epidemiological studies have demonstrated that these markers are associated with the risk of stroke, but the value of these markers in a clinical setting has not yet been proven. Further research is needed to determine whether immune system modulators can lower the risk of stroke in individuals with elevated concentrations of inflammatory markers. Here, we review the association between infection, systemic inflammation, and ischaemic stroke, and discuss the currently recommended preventive methods to decrease the risk of stroke associated with systemic inflammation. 10.1038/nrneurol.2016.125
    Hypoxia-dependent regulation of inflammatory pathways in immune cells. Taylor Cormac T,Doherty Glen,Fallon Padraic G,Cummins Eoin P The Journal of clinical investigation Uncontrolled inflammation underpins a diverse range of diseases where effective therapy remains an unmet clinical need. Hypoxia is a prominent feature of the inflammatory microenvironment that regulates key transcription factors including HIF and NF-κB in both innate and adaptive immune cells. In turn, altered activity of the pathways controlled by these factors can affect the course of inflammation through the regulation of immune cell development and function. In this review, we will discuss these pathways and the oxygen sensors that confer hypoxic sensitivity in immune cells. Furthermore, we will describe how hypoxia-dependent pathways contribute to immunity and discuss their potential as therapeutic targets in inflammatory and infectious disease. 10.1172/JCI84433
    Immune Factors in Deep Vein Thrombosis Initiation. Budnik Ivan,Brill Alexander Trends in immunology Deep vein thrombosis (DVT) is a major origin of morbidity and mortality. While DVT has long been considered as blood coagulation disorder, several recent lines of evidence demonstrate that immune cells and inflammatory processes are involved in DVT initiation. Here, we discuss these mechanisms, in particular, the role of immune cells in endothelial activation, and the immune cascades leading to expression of adhesion receptors on endothelial cells. We analyze the specific recruitment and functional roles of different immune cells, such as mast cells and leukocytes, in DVT. Importantly, we also speculate how immune modulation could be used for DVT prevention with a lower risk of bleeding complications than conventional therapeutic approaches. 10.1016/j.it.2018.04.010