Abstract
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.
Atheroprogression is a consequence of nonresolved inflammation, and currently a comprehensive overview of the mechanisms preventing resolution is missing. However, in acute inflammation, resolution ...is known to be orchestrated by a switch from inflammatory to resolving lipid mediators. Therefore, we hypothesized that lesional lipid mediator imbalance favors atheroprogression.
To understand the lipid mediator balance during atheroprogression and to establish an interventional strategy based on the delivery of resolving lipid mediators.
Aortic lipid mediator profiling of aortas from Apoe
mice fed a high-fat diet for 4 weeks, 8 weeks, or 4 months revealed an expansion of inflammatory lipid mediators, Leukotriene B4 and Prostaglandin E2, and a concomitant decrease of resolving lipid mediators, Resolvin D2 (RvD2) and Maresin 1 (MaR1), during advanced atherosclerosis. Functionally, aortic Leukotriene B4 and Prostaglandin E2 levels correlated with traits of plaque instability, whereas RvD2 and MaR1 levels correlated with the signs of plaque stability. In a therapeutic context, repetitive RvD2 and MaR1 delivery prevented atheroprogression as characterized by halted expansion of the necrotic core and accumulation of macrophages along with increased fibrous cap thickness and smooth muscle cell numbers. Mechanistically, RvD2 and MaR1 induced a shift in macrophage profile toward a reparative phenotype, which secondarily stimulated collagen synthesis in smooth muscle cells.
We present evidence for the imbalance between inflammatory and resolving lipid mediators during atheroprogression. Delivery of RvD2 and MaR1 successfully prevented atheroprogression, suggesting that resolving lipid mediators potentially represent an innovative strategy to resolve arterial inflammation.
There is emerging evidence that neutrophil extracellular traps (NETs) play important roles in inflammatory processes. Here we report that neutrophils have to be simultaneously activated by ...integrin-mediated outside-in– and G-protein–coupled receptor (GPCR) signaling to induce NET formation in acute lung injury (ALI), which is associated with a high mortality rate in critically ill patients. NETs consist of decondensed chromatin decorated with granular and cytosolic proteins and they can trap extracellular pathogens. The prerequisite for NET formation is the activation of neutrophils and the release of their DNA. In a neutrophil- and platelet-dependent mouse model of ventilator-induced lung injury (VILI), NETs were found in the lung microvasculature, and circulating NET components increased in the plasma. In this model, blocking integrin-mediated outside-in or either GPCR-signaling or heteromerization of platelet chemokines decreased NET formation and lung injury. Targeting NET components by DNAse1 application or neutrophil elastase–deficient mice protected mice from ALI, whereas DNase1−/−/Trap1m/m mice had an aggravated ALI, suggesting that NETs directly influence the severity of ALI. These data suggest that NETs form in the lungs during VILI, contribute to the disease process, and thus may be a promising new direction for the treatment of ALI.
•NET formation is required for neutrophil recruitment during sterile inflammation.•Platelet-induced NET formation requires stimulation of neutrophils by platelet chemokines and outside-in signaling via the integrin Mac-1.
Chemokines and their receptors represent a potential target for immunotherapy in chronic inflammation. They comprise a large family of cytokines with chemotactic activity, and their cognate receptors ...are expressed on all cells of the body. This network dictates leukocyte recruitment and activation, angiogenesis, cell proliferation and maturation. Dysregulation of chemokine and chemokine receptor expression as well as function participates in many pathologies including cancer, autoimmune diseases and chronic inflammation. In atherosclerosis, a lipid-driven chronic inflammation of middle-sized and large arteries, chemokines and their receptors participates in almost all stages of the disease from initiation of fatty streaks to mature atherosclerotic plaque formation. Atherosclerosis and its complications are the main driver of mortality and morbidity in cardiovascular diseases (CVD). Hence, exploring new fields of therapeutic targeting of atherosclerosis is of key importance. This review gives an overview of the recent advances on the role of key chemokines and chemokine receptors in atherosclerosis, addresses chemokine-based biomarkers at biochemical, imaging and genetic level in human studies, and highlights the clinial trials targeting atherosclerosis.
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•Chemokine (receptors) are important modifiers of atherosclerosis.•Chemokine (receptors) could be important biomarkers or imaging tracers in human CVD.•Genetic alterations in genes coding for chemokine (receptors) can be associated with different CVD risk.•Clinical trials reveal therapeutic targeting options of chemokine (receptors) in human CVD.
Heart failure following myocardial infarction (MI) remains one of the major causes of death worldwide, and its treatment is a crucial challenge of cardiovascular medicine. An attractive therapeutic ...strategy is to stimulate endogenous mechanisms of myocardial regeneration.
This study evaluates the potential therapeutic treatment with annexin A1 (AnxA1) to induce cardiac repair after MI.
AnxA1 knockout (AnxA1
) and wild-type mice underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac functionality was assessed by longitudinal echocardiographic measurements. Histological, fluorescence-activated cell sorting, dot blot analysis, and in vitro/ex vivo studies were used to assess the myocardial neovascularization, macrophage content, and activity in response to AnxA1.
AnxA1
mice showed a reduced cardiac functionality and an expansion of proinflammatory macrophages in the ischemic area. Cardiac macrophages from AnxA1
mice exhibited a dramatically reduced ability to release the proangiogenic mediator vascular endothelial growth factor (VEGF)-A. However, AnxA1 treatment enhanced VEGF-A release from cardiac macrophages, and its delivery in vivo markedly improved cardiac performance. The positive effect of AnxA1 treatment on cardiac performance was abolished in wild-type mice transplanted with bone marrow derived from Cx
cr1cre
Vegf
or in mice depleted of macrophages. Similarly, cardioprotective effects of AnxA1 were obtained in pigs in which full-length AnxA1 was overexpressed by use of a cardiotropic adeno-associated virus.
AnxA1 has a direct action on cardiac macrophage polarization toward a pro-angiogenic, reparative phenotype. AnxA1 stimulated cardiac macrophages to release high amounts of VEGF-A, thus inducing neovascularization and cardiac repair.
The global coronavirus disease 2019 (COVID-19) pandemic has deranged the recent history of humankind, afflicting more than 27 million individuals to date. While the majority of COVID-19 patients ...recuperate, a considerable number of patients develop severe complications. Bilateral pneumonia constitutes the hallmark of severe COVID-19 disease but an involvement of other organ systems, namely the cardiovascular system, kidneys, liver, and central nervous system, occurs in at least half of the fatal COVID-19 cases. Besides respiratory failure requiring ventilation, patients with severe COVID-19 often display manifestations of systemic inflammation and thrombosis as well as diffuse microvascular injury observed postmortem. In this review, we survey the mechanisms that may explain how viral entry and activation of endothelial cells by severe acute respiratory syndrome coronavirus 2 can give rise to a series of events including systemic inflammation, thrombosis, and microvascular dysfunction. This pathophysiological scenario may be particularly harmful in patients with overt cardiovascular disease and may drive the fatal aspects of COVID-19. We further shed light on the role of the renin-angiotensin aldosterone system and its inhibitors in the context of COVID-19 and discuss the potential impact of antiviral and anti-inflammatory treatment options. Acknowledging the comorbidities and potential organ injuries throughout the course of severe COVID-19 is crucial in the clinical management of patients affecting treatment approaches and recovery rate.
Inflammatory Chemokines in Atherosclerosis Gencer, Selin; Evans, Bryce R; van der Vorst, Emiel P C ...
Cells (Basel, Switzerland),
01/2021, Letnik:
10, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Atherosclerosis is a long-term, chronic inflammatory disease of the vessel wall leading to the formation of occlusive or rupture-prone lesions in large arteries. Complications of atherosclerosis can ...become severe and lead to cardiovascular diseases (CVD) with lethal consequences. During the last three decades, chemokines and their receptors earned great attention in the research of atherosclerosis as they play a key role in development and progression of atherosclerotic lesions. They orchestrate activation, recruitment, and infiltration of immune cells and subsequent phenotypic changes, e.g., increased uptake of oxidized low-density lipoprotein (oxLDL) by macrophages, promoting the development of foam cells, a key feature developing plaques. In addition, chemokines and their receptors maintain homing of adaptive immune cells but also drive pro-atherosclerotic leukocyte responses. Recently, specific targeting, e.g., by applying cell specific knock out models have shed new light on their functions in chronic vascular inflammation. This article reviews recent findings on the role of immunomodulatory chemokines in the development of atherosclerosis and their potential for targeting.
Inflammation has been closely linked to auto-immunogenic processes in atherosclerosis. Plasmacytoid dendritic cells (pDCs) are specialized to produce type-I interferons in response to pathogenic ...single-stranded nucleic acids, but can also sense self-DNA released from dying cells or in neutrophil extracellular traps complexed to the antimicrobial peptide Cramp/LL37 in autoimmune disease. However, the exact role of pDCs in atherosclerosis remains elusive.
Here we demonstrate that pDCs can be detected in murine and human atherosclerotic lesions. Exposure to oxidatively modified low-density lipoprotein enhanced the capacity of pDCs to phagocytose and prime antigen-specific T cell responses. Plasmacytoid DCs can be stimulated to produce interferon-α by Cramp/DNA complexes, and we further identified increased expression of Cramp and formation of neutrophil extracellular traps in atherosclerotic arteries. Whereas Cramp/DNA complexes aggravated atherosclerotic lesion formation in apolipoprotein E-deficient mice, pDC depletion and Cramp-deficiency in bone marrow reduced atherosclerosis and anti-double-stranded DNA antibody titers. Moreover, the specific activation of pDCs and interferon-α treatment promoted plaque growth, associated with enhanced anti-double-stranded-DNA antibody titers. Accordingly, anti-double-stranded DNA antibodies were elevated in patients with symptomatic versus asymptomatic carotid artery stenosis.
Self-DNA (eg, released from dying cells or in neutrophil extracellular traps) and an increased expression of the antimicrobial peptide Cramp/LL37 in atherosclerotic lesions may thus stimulate a pDC-driven pathway of autoimmune activation and the generation of anti-double-stranded-DNA antibodies, critically aggravating atherosclerosis lesion formation. These key factors may thus represent novel therapeutic targets.
Neutrophils have been reported to contribute to early atherosclerotic lesion formation. Mechanisms of neutrophil-driven atherosclerosis remain unclear so far.
Investigation of the role of the ...neutrophil granule protein cathelicidin (CRAMP in mouse, LL37 in human) in atherosclerosis.
Compared to Apoe(-/-) mice, Cramp(-/-) Apoe(-/-) mice exhibit reduced lesion sizes with lower macrophage numbers. In atherosclerotic aortas, we could detect CRAMP specifically in neutrophils, but not in monocytes or macrophages. By use of intravital microscopy, CRAMP was found to be deposited by activated neutrophils on inflamed endothelium of large arteries. In this location cathelicidins promote adhesion of classical monocytes and neutrophils, but not nonclassical monocytes in a formyl-peptide receptor-dependent manner.
Cathelicidins promote atherosclerosis by enhancement of the recruitment of inflammatory monocytes.
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