Immune mechanisms in heart failure Zhang, Yingying; Bauersachs, Johann; Langer, Harald F.
European journal of heart failure,
November 2017, Volume:
19, Issue:
11
Journal Article
Peer reviewed
Open access
Elevated levels of circulating pro‐inflammatory biomarkers in patients with both ischaemic and non‐ischaemic heart failure (HF) correlate with disease severity and prognosis. Experimental studies ...have shown activation of immune response mechanisms in the heart to provoke cardiac adverse remodelling and cause left ventricular dysfunction. Consequently, most of the clinical trials targeting elements of the immune response in HF attempted to modulate the inflammatory response. Surprisingly, clinical studies targeting immune effectors were either neutral or even increased pre‐specified clinical endpoints, and some studies resulted in worsening of HF. This review discusses immune mediators involved in the pathogenesis and progression of HF and potential therapeutic applications targeting inflammation in HF. Besides more obvious settings featuring immune activation such as inflammatory or ischaemic cardiomyopathy, the relevance of immune activation in acute or chronic HF of other origins, including volume overload or valvular heart disease, is highlighted. Understanding how cell‐specific and molecular mechanisms of the immune response interfere with cardiac remodelling in HF may open new avenues to design biomarkers or druggable targets.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Cardiovascular disease remains the main cause of death worldwide. For this reason, strategies for the primary prevention of atherosclerosis and atherosclerosis-related pathologies like stroke or ...myocardial infarction are needed.
Platelets are key players of atherosclerosis-related vascular thrombotic pathologies and their role as targets in secondary prevention of atherosclerosis-related complications is uncontested. However, platelets also play an important role in the initiation and progression of atherosclerosis. Currently, though, there is no generally valid recommendation for the use of antiplatelet therapy in primary prevention of cardiovascular disease. Recent clinical studies have shown that the benefit from antiplatelet therapy in primary prevention is counteracted by the entailed bleeding risk.
This review addresses the important role platelets play in initiating and sustaining vascular inflammation, which drives atherosclerosis. Specifically, platelet-lipid interactions as well as platelet-endothelium interactions in the context of atherosclerosis are illustrated. We also depict how platelets help recruit immune cells like monocytes, neutrophils or dendritic cells to the subendothelial space. Finally, we portray the role of complement and platelets in atherosclerosis. Platelets appear to act as mediators of tissue homeostasis and may also modulate the microenvironment of the atherosclerotic plaque.
Overall, this review addresses the role of platelets in atherosclerosis with particular focus on potential targets for pharmacological interventions into platelet functions distinct from aggregation. By eliminating the bleeding risk of antiplatelet therapy, platelets are likely to regain a role in primary prevention of cardiovascular disease.
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•Currently, antiplatelet therapy is not indicated for primary prevention of atherosclerosis due to its entailed bleeding risk.•However, platelets impact on the initiation as well as progression of atherosclerosis in various ways.•In the future, new drugs may target only inflammatory roles of platelets without affecting primary hemostasis. Then the role of antiplatelets therapy for primary prevention of atherosclerosis would have to be reconsidered.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, SAZU, SBCE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Beyond platelets function in hemostasis, there is emerging evidence to suggest that platelets contribute crucially to inflammation and immune responses. Therefore, considering the detrimental role of ...inflammatory conditions in severe neurological disorders such as multiple sclerosis or stroke, this review outlines platelets involvement in neuroinflammation. For this, distinct mechanisms of platelet-mediated thrombosis and inflammation are portrayed, focusing on the interaction of platelet receptors with other immune cells as well as brain endothelial cells. Furthermore, we draw attention to the intimate interplay between platelets and the complement system as well as between platelets and plasmatic coagulation factors in the course of neuroinflammation. Following the thorough exposition of preclinical approaches which aim at ameliorating disease severity after inducing experimental autoimmune encephalomyelitis (a counterpart of multiple sclerosis in mice) or brain ischemia-reperfusion injury, the clinical relevance of platelet-mediated neuroinflammation is addressed. Thus, current as well as future propitious translational and clinical strategies for the treatment of neuro-inflammatory diseases by affecting platelet function are illustrated, emphasizing that targeting platelet-mediated neuroinflammation could become an efficient adjunct therapy to mitigate disease severity of multiple sclerosis or stroke associated brain injury.
Complement, inflammation and thrombosis Rawish, Elias; Sauter, Manuela; Sauter, Reinhard ...
British journal of pharmacology,
July 2021, Volume:
178, Issue:
14
Journal Article
Peer reviewed
Open access
A mutual relationship exists between immune activation and mechanisms of thrombus formation. In particular, elements of the innate immune response such as the complement system can modulate platelet ...activation and subsequently thrombus formation. Several components of the complement system including C3 or the membrane attack complex have been reported to be associated with platelets and become functionally active in the micromilieu of platelet activation. The exact mechanisms how this interplay is regulated and its consequences for tissue inflammation, damage or recovery remain to be defined. This review addresses the current state of knowledge on this topic and puts it into context with diseases featuring both thrombosis and complement activation.
Linked Articles
This article is part of a themed issue on Canonical and non‐canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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Introduction
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Adhesion molecules
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Leukocyte margination, capture and cell rolling
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Activation and adhesion of leukocytes
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Transmigration
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Endogenous inhibitors of leukocyte adhesion
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...Platelet–leukocyte crosstalk
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Conclusions
At sites of inflammation, infection or vascular injury local proinflammatory or pathogen‐derived stimuli render the luminal vascular endothelial surface attractive for leukocytes. This innate immunity response consists of a well‐defined and regulated multi‐step cascade involving consecutive steps of adhesive interactions between the leukocytes and the endothelium. During the initial contact with the activated endothelium leukocytes roll along the endothelium via a loose bond which is mediated by selectins. Subsequently, leukocytes are activated by chemokines presented on the luminal endothelial surface, which results in the activation of leukocyte integrins and the firm leukocyte arrest on the endothelium. After their firm adhesion, leukocytes make use of two transmigration processes to pass the endothelial barrier, the transcellular route through the endothelial cell body or the paracellular route through the endothelial junctions. In addition, further circulating cells, such as platelets arrive early at sites of inflammation contributing to both coagulation and to the immune response in parts by facilitating leukocyte–endothelial interactions. Platelets have thereby been implicated in several inflammatory pathologies. This review summarizes the major mechanisms and molecules involved in leukocyte–endothelial and leukocyte‐platelet interactions in inflammation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
During the prolonged course of atherosclerotic disease,platelets are of central importance as they contribute to the initiation of the disease, to its progression and acute exacerbation but also ...provide potential regenerative mechanisms. Platelets secrete chemokines and cytokines that mediate vascular inflammation and are in turn activated by substances released from cells of the vascular wall.These interactions represent positive and negative feedback loops, which in case of dysregulation may lead to development and progression of disease. Furthermore, platelet adhesion to the endothelium is critical for the initiation of atherosclerotic lesion formation in vivo. Even prior to endothelial denudation, platelet adhesion governed by disturbed flow at predilection sites for atherosclerosis induces recruitment of proatherosclerotic cells and release of proinflammatory mediators from all involved cell types.Finally,the pathogenetic role of platelets for late atheroclerotic events including plaque rupture, microembolism or spasms within the microcirculation is well established. However, increasing evidence indicates that platelets mediate on the other hand potential regenerative mechanisms. Platelets recruit circulating progenitor cells to sites of vascular injury. Furthermore, they influence their biological activity and maturation. Therefore,platelets contribute at all stages of vascular disease by interfering with highly dynamic processes. Understanding interactions of platelets with other circulating cells and the vascular wall is a prerequisite to understand cardiovascular disease and to identify potential therapeutic targets.
The complement system is a versatile part of our immune system. Various intersection points of complement with other cells and molecules of the immune response are well described. Platelets are ...classically conceived as cells of hemostasis. In recent years, however, several functions of platelets “beyond thrombosis” were discovered.
This review depicts the crosstalk of platelets with components of the immune system in the context of thrombo-inflammation. In particular, the various ways, in which platelets interact with the complement system, are illustrated. Platelets cannot only aggravate vascular inflammation and cardiovascular diseases, but they also contribute to organ remodeling and tissue homeostasis. Here, we portray the role of complement factors associated with platelet activation in tissue remodeling. Importantly, the clinical relevance of this platelet-complement crosstalk is addressed. A focus lies on thrombo-inflammatory disorders, other diseases with thrombo-embolic mechanisms or complications, but also autoimmune diseases. Finally, we draw attention to the growing body of evidence on the role of complement-platelet crosstalk in cardiovascular diseases. For future clinical, translational and basic science approaches, this crosstalk may prove a fruitful area of research in order to procure novel therapeutic and diagnostic targets in cardiovascular medicine and previously less addressed diseases featuring a platelet-complement axis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
P2X receptors belong to a family of cation channel proteins, which respond to extracellular adenosine 5′-triphosphate (ATP). These receptors have gained increasing attention in basic and ...translational research, as they are central to a variety of important pathophysiological processes such as the modulation of cardiovascular physiology, mediation of nociception, platelet and macrophage activation, or neuronal–glial integration. While P2X1 receptor activation is long known to drive platelet aggregation, P2X7 receptor antagonists have recently been reported to inhibit platelet activation. Considering the role of both P2X receptors and platelet-mediated inflammation in neuronal diseases such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and stroke, targeting purinergic receptors may provide a valuable novel therapeutic approach in these diseases. Therefore, the present review illuminates the role of platelets and purinergic signaling in these neurological conditions to evaluate potential translational implications.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Platelets contribute to processes beyond thrombus formation and may play a so far underestimated role as an immune cell in various circumstances. This review outlines immune functions of platelets in ...host defense, but also how they may contribute to mechanisms of infectious diseases. A particular emphasis is placed on the interaction of platelets with other immune cells. Furthermore, this article outlines the features of atherosclerosis as an inflammatory vascular disease highlighting the role of platelet crosstalk with cellular and soluble factors involved in atheroprogression. Understanding, how platelets influence these processes of vascular remodeling will shed light on their role for tissue homeostasis beyond intravascular thrombosis. Finally, translational implications of platelet-mediated inflammation in atherosclerosis are discussed.
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