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Nadine Herr

Bio: Nadine Herr is an academic researcher from University of Freiburg. The author has contributed to research in topics: Inflammation & Serotonin. The author has an hindex of 6, co-authored 11 publications receiving 544 citations.

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Journal ArticleDOI
TL;DR: Serotonin can also suppress the release of tumor necrosis factor-α and interleukin-1β by activating serotonin receptors, and neutrophil recruitment and T-cell activation can both be mediated by serotonin.
Abstract: Serotonin (5-Hydroxytryptamine, 5-HT) plays an important role in many organs as a peripheral hormone. Most of the body's serotonin is circulating in the bloodstream, transported by blood platelets and is released upon activation. The functions of serotonin are mediated by members of the 7 known mammalian serotonin receptor subtype classes (15 known subtypes), the serotonin transporter (SERT) and by covalent binding of serotonin to different effector proteins. Almost all immune cells express at least one serotonin component. In recent years, a number of immunoregulatory functions have been ascribed to serotonin. In monocytes/macrophages for example serotonin modulates cytokine secretion. Serotonin can also suppress the release of TNF-α and IL-1β by activating serotonin receptors. Furthermore, neutrophil recruitment and T-Cell activation can both be mediated by serotonin. These are only a few of the known immunomodulatory roles of serotonin that we will review here.

276 citations

Journal ArticleDOI
TL;DR: The novel finding that CD40L binds to the EQLKKSKTL motif on Mac-1 mediating leukocyte recruitment and atherogenesis is presented, potentially avoiding the unwanted immunologic and thrombotic effects of global inhibition ofCD40L.
Abstract: Rationale:CD40L figures prominently in chronic inflammatory diseases such as atherosclerosis. However, since CD40L potently regulates immune function and hemostasis by interaction with CD40 receptor and the platelet integrin GPIIb/IIIa, its global inhibition compromises host defense and generated thromboembolic complications in clinical trials. We recently reported that CD40L mediates atherogenesis independently of CD40 and proposed Mac-1 as an alternate receptor. Objective:Here, we molecularly characterized the CD40L-Mac-1 interaction and tested whether its selective inhibition by a small peptide modulates inflammation and atherogenesis in vivo. Methods and Results:CD40L concentration-dependently bound to Mac-1 I-domain in solid phase binding assays, and a high-affinity interaction was revealed by surface-plasmon-resonance analysis. We identified the motif EQLKKSKTL, an exposed loop between the α1 helix and the β-sheet B, on Mac-1 as binding site for CD40L. A linear peptide mimicking this sequence, M7, s...

94 citations

Journal ArticleDOI
TL;DR: Serotonin is identified as a potent therapeutic target in neutrophil-dependent thromboinflammation during myocardial reperfusion injury and patients with depression using serotonin reuptake inhibition are presented with suppressed levels of CD11b surface expression on neutrophils and lower myeloperoxidase levels in blood.
Abstract: Background: Platelets store large amounts of serotonin that they release during thrombus formation or acute inflammation. This facilitates hemostasis and modulates the inflammatory response. Method...

84 citations

Journal ArticleDOI
10 Feb 2014-PLOS ONE
TL;DR: Acute fluoxetine treatment increased plasma serotonin concentrations and promoted leukocyte-endothelial interactions in-vivo, suggesting that serotonin is a promoter of acute inflammation.
Abstract: Objective Activated platelets release serotonin at sites of inflammation where it acts as inflammatory mediator and enhances recruitment of neutrophils. Chronic treatment with selective serotonin reuptake inhibitors (SSRI) depletes the serotonin storage pool in platelets, leading to reduced leukocyte recruitment in murine experiments. Here, we examined the direct and acute effects of SSRI on leukocyte recruitment in murine peritonitis. Methods C57Bl/6 and Tph1−/− (Tryptophan hydroxylase1) mice underwent acute treatment with the SSRI fluoxetine or vehicle. Serotonin concentrations were measured by ELISA. Leukocyte rolling and adhesion on endothelium was analyzed by intravital microscopy in mesentery venules with and without lipopolysaccharide challenge. Leukocyte extravasation in sterile peritonitis was measured by flow cytometry of abdominal lavage fluid. Results Plasma serotonin levels were elevated 2 hours after fluoxetine treatment (0.70±0.1 µg/ml versus 0.27±0.1, p = 0.03, n = 14), while serum serotonin did not change. Without further stimulation, acute fluoxetine treatment increased the number of rolling leukocytes (63±8 versus 165±17/0.04 mm2min−1) and decreased their velocity (61±6 versus 28±1 µm/s, both p<0.0001, n = 10). In Tph1−/− mice leukocyte rolling was not significantly influenced by acute fluoxetine treatment. Stimulation with lipopolysaccharide decreased rolling velocity and induced leukocyte adhesion, which was enhanced after fluoxetine pretreatment (27±3 versus 36±2/0.04 mm2, p = 0.008, n = 10). Leukocyte extravasation in sterile peritonitis, however, was not affected by acute fluoxetine treatment. Conclusions Acute fluoxetine treatment increased plasma serotonin concentrations and promoted leukocyte-endothelial interactions in-vivo, suggesting that serotonin is a promoter of acute inflammation. E-selectin was upregulated on endothelial cells in the presence of serotonin, possibly explaining the observed increase in leukocyte-endothelial interactions. However transmigration of neutrophils in sterile peritonitis was not affected by higher serotonin concentrations, indicating that the effect of fluoxetine was restricted to early steps in the leukocyte recruitment. Whether SSRI use in humans alters leukocyte recruitment remains to be investigated.

27 citations


Cited by
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Journal ArticleDOI
TL;DR: Current understanding of the roles of platelet secretion in health and disease is summarized, and some of the hypotheses that may explain how platelets may control the release of its many secreted components in a context-specific manner are discussed to allow platelets to play multiple roles in health.

577 citations

Journal ArticleDOI
TL;DR: The molecular mechanisms involved in plaque vulnerability and the development of atherothrombosis are discussed and plaques with reduced collagen content are thought to be more vulnerable than those with a thick collagen cap.
Abstract: Atherosclerosis is a maladaptive, nonresolving chronic inflammatory disease that occurs at sites of blood flow disturbance. The disease usually remains silent until a breakdown of integrity at the arterial surface triggers the formation of a thrombus. By occluding the lumen, the thrombus or emboli detaching from it elicits ischaemic symptoms that may be life-threatening. Two types of surface damage can cause atherothrombosis: plaque rupture and endothelial erosion. Plaque rupture is thought to be caused by loss of mechanical stability, often due to reduced tensile strength of the collagen cap surrounding the plaque. Therefore, plaques with reduced collagen content are thought to be more vulnerable than those with a thick collagen cap. Endothelial erosion, on the other hand, may occur after injurious insults to the endothelium instigated by metabolic disturbance or immune insults. This review discusses the molecular mechanisms involved in plaque vulnerability and the development of atherothrombosis.

562 citations

Journal ArticleDOI
TL;DR: The evidence detailed in this review underscores macrophage polarization as a target of interest for immunotherapy because of the high plasticity of macrophages and their potential to be exploited to reduce chronic/detrimental inflammation.
Abstract: Macrophages are extremely heterogeneous and plastic cells with an important role not only in physiological conditions, but also during inflammation (both for initiation and resolution). In the early 1990s, two different phenotypes of macrophages were described: one of them called classically activated (or inflammatory) macrophages (M1) and the other alternatively activated (or wound-healing) macrophages (M2). Currently, it is known that functional polarization of macrophages into only two groups is an over-simplified description of macrophage heterogeneity and plasticity; indeed, it is necessary to consider a continuum of functional states. Overall, the current available data indicate that macrophage polarization is a multifactorial process in which a huge number of factors can be involved producing different activation scenarios. Once a macrophage adopts a phenotype, it still retains the ability to continue changing in response to new environmental influences. The reversibility of polarization has a critical therapeutic value, especially in diseases in which an M1/M2 imbalance plays a pathogenic role. In this review, we assess the high plasticity of macrophages and their potential to be exploited to reduce chronic/detrimental inflammation. On the whole, the evidence detailed in this review underscores macrophage polarization as a target of interest for immunotherapy.

462 citations

Journal ArticleDOI
TL;DR: There is growing recognition of the critical role of platelets in inflammation and immune responses, and recent studies have indicated that antiplatelet medications may reduce mortality from infections and sepsis, which suggests possible clinical relevance of modifying platelet responses to inflammation.
Abstract: There is growing recognition of the critical role of platelets in inflammation and immune responses. Recent studies have indicated that antiplatelet medications may reduce mortality from infections and sepsis, which suggests possible clinical relevance of modifying platelet responses to inflammation. Platelets release numerous inflammatory mediators that have no known role in haemostasis. Many of these mediators modify leukocyte and endothelial responses to a range of different inflammatory stimuli. Additionally, platelets form aggregates with leukocytes and form bridges between leukocytes and endothelium, largely mediated by platelet P-selectin. Through their interactions with monocytes, neutrophils, lymphocytes and the endothelium, platelets are therefore important coordinators of inflammation and both innate and adaptive immune responses.

382 citations

Journal ArticleDOI
TL;DR: Mechanisms underlying hyperlipidemia-mediated neutrophilia and how neutrophils may enter atherosclerotic lesions are described and possible mechanisms of neutrophil-driven atherogenesis and plaque destabilization are highlighted.
Abstract: Because of their rare detection in atherosclerotic lesions, the involvement of neutrophils in the pathophysiology of atherosclerosis has been largely denied. However, over the past couple of years, studies have provided convincing evidence for the presence of neutrophils in atherosclerotic plaques and further revealed the causal contribution of neutrophils during various stages of atherosclerosis. This review describes mechanisms underlying hyperlipidemia-mediated neutrophilia and how neutrophils may enter atherosclerotic lesions. It also highlights possible mechanisms of neutrophil-driven atherogenesis and plaque destabilization. Knowledge of the contribution of neutrophils to atherosclerosis will allow for exploration of new avenues in the treatment of atherogenesis and atherothrombosis.

377 citations