Functional Relevance of the Anaphylatoxin Receptor C3aR for Platelet Function and Arterial Thrombus Formation Marks an Intersection Point Between Innate Immunity and Thrombosis

Sauter, Manuela; Emschermann, Fréderic; Nording, Henry; Ebenhöch, Sonja; Kraft, Peter; Münzer, Patrick; Mauler, Maximilian; Rheinlaender, Johannes; Madlung, Johannes; Edlich, Frank; Schäffer, Tilman E.; Meuth, Sven G.; Duerschmied, Daniel; Geisler, Tobias; Gawaz, Meinrad; Kleinschnitz, Christoph; Lambris, John D.; Langer, Harald F.

doi:10.1161/circulationaha.118.034600

Cited by 90 publications

(108 citation statements)

References 58 publications

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“…Endothelial cells are activated during septic settings and respond to C3a [66] and are crucial interfaces for the interaction between Nme and the host [67]. Thus, by modulation of vascular permeability [60] or intravascular coagulation in combination with C3aR-bearing platelets [68], C3aR might impact on the course of Nme sepsis in a cytokine/chemokine-independent fashion.…”

Section: Discussionmentioning

confidence: 99%

Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections

et al. 2019

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The complement system is pivotal in the defense against invasive disease caused by Neisseria meningitidis (Nme, meningococcus), particularly via the membrane attack complex. Complement activation liberates the anaphylatoxins C3a and C5a, which activate three distinct G-protein coupled receptors, C3aR, C5aR1 and C5aR2 (anaphylatoxin receptors, ATRs). We recently discovered that C5aR1 exacerbates the course of the disease, revealing a downside of complement in Nme sepsis. Here, we compared the roles of all three ATRs during mouse nasal colonization, intraperitoneal infection and human whole blood infection with Nme. Deficiency of complement or ATRs did not alter nasal colonization, but significantly affected invasive disease: Compared to WT mice, the disease was aggravated in C3ar −/mice, whereas C5ar1 −/and C5ar2 −/mice showed increased resistance to meningococcal sepsis. Surprisingly, deletion of either of the ATRs resulted in lower cytokine/chemokine responses, irrespective of the different susceptibilities of the mice. This was similar in ex vivo human whole blood infection using ATR inhibitors. Neutrophil responses to Nme were reduced in C5ar1 −/mouse blood. Upon stimulation with C5a plus Nme, mouse macrophages displayed reduced phosphorylation of ERK1/2, when C5aR1 or C5aR2 were ablated or inhibited, suggesting that both C5a-receptors prime an initial macrophage response to Nme. Finally, in vivo blockade of C5aR1 alone (PMX205) or along with C5aR2 (A8 Δ71−73) resulted in ameliorated disease, whereas neither antagonizing C3aR (SB290157) nor its activation with a "super-agonist" peptide (WWGKKYRASKLGLAR) demonstrated a benefit. Thus, C5aR1 and C5aR2 augment disease pathology and are interesting targets for treatment, whereas C3aR is protective in experimental meningococcal sepsis.

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Section: Discussionmentioning

confidence: 99%

Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections

et al. 2019

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“…Platelet‐derived HMGB1 was instrumental on acceleration of adhesion speed and increased spreading area of platelets on collagen and von Willebrand factor (VWF). Similarly, 3D topographic measurements using SICM have shown that platelets deficient in anaphylatoxin receptor C3aR exhibit a reduced spreading area on fibrinogen after thrombin stimulation compared to their normal platelets . These observations indicate a role of complement activation fragment C3a and C3aR for platelet function during thrombus formation.…”

Section: Techniques For Measuring the Biomechanical Properties Of Sinmentioning

confidence: 82%

Quantifying single‐platelet biomechanics: An outsider’s guide to biophysical methods and recent advances

Sachs

Denker

Greinacher

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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Platelets are the key cellular components of blood primarily contributing to formation of stable hemostatic plugs at the site of vascular injury, thus preventing excessive blood loss. On the other hand, excessive platelet activation can contribute to thrombosis. Platelets respond to many stimuli that can be of biochemical, cellular, or physical origin. This drives platelet activation kinetics and plays a vital role in physiological and pathological situations. Currently used bulk assays are inadequate for comprehensive biomechanical assessment of single platelets. Individual platelets interact and respond differentially while modulating their biomechanical behavior depending on dynamic changes that occur in surrounding microenvironments. Quantitative description of such a phenomenon at single‐platelet regime and up to nanometer resolution requires methodological approaches that can manipulate individual platelets at submicron scales. This review focusses on principles, specific examples, and limitations of several relevant biophysical methods applied to single‐platelet analysis such as micropipette aspiration, atomic force microscopy, scanning ion conductance microscopy and traction force microscopy. Additionally, we are introducing a promising single‐cell approach, real‐time deformability cytometry, as an emerging biophysical method for high‐throughput biomechanical characterization of single platelets. This review serves as an introductory guide for clinician scientists and beginners interested in exploring one or more of the above‐mentioned biophysical methods to address outstanding questions in single‐platelet biomechanics.

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“…Complement system inhibitors were also able to inhibit the intrinsic coagulation pathway, thrombin activity, and protein S [9][10][11]. In addition to the coagulation cascade, complement factors were found to increase platelet activity and aggregation [20][21][22][23][24], prothrombinase activity, and the release of platelet-derived procoagulant granules [25,26], as well as stimulate endothelial cells to release prothrombotic von Willebrand factor and express P-selectin [86][87][88]. This evidence collectively suggests that increased complement activity leads to increased coagulation cascade activity and platelet aggregation, i.e., a prothrombotic state.…”

Section: Discussionmentioning

confidence: 99%

“…More recent studies have also shown that C3 deficiency in mice causes a prolonged bleeding time, reduced thrombus incidence and size, reduced fibrin and platelet deposition, and reduced platelet activation [23]. Other studies have further demonstrated that platelets have receptors for C3a that in turn can mediate platelet activation [24]. Thus, both C3 and the MAC of the complement system appear capable of activating platelets (Table 1, Figure 2).…”

Section: Complement and Plateletsmentioning

confidence: 96%

Does Complement-Mediated Hemostatic Disturbance Occur in Traumatic Brain Injury? A Literature Review and Observational Study Protocol

Fletcher‐Sandersjöö

Maegele

Bellander

2020

IJMS

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Despite improvements in medical triage and tertiary care, traumatic brain injury (TBI) remains associated with significant morbidity and mortality. Almost two-thirds of patients with severe TBI develop some form of hemostatic disturbance, which contributes to poor outcome. In addition, the complement system, which is abundant in the healthy brain, undergoes significant intra- and extracranial amplification following TBI. Previously considered to be structurally similar but separate systems, evidence of an interaction between the complement and coagulation systems in non-TBI cohorts has accumulated, with the activation of one system amplifying the activation of the other, independent of their established pathways. However, it is not known whether this interaction exists in TBI. In this review we summarize the available literature on complement activation following TBI, and the crosstalk between the complement and coagulation systems. We demonstrate how the complement system interacts with the coagulation cascade by activating the intrinsic coagulation pathway and by bypassing the initial cascade and directly producing thrombin as well. This crosstalk also effects platelets, where evidence points to a relationship with the complement system on multiple levels, with complement anaphylatoxins being able to induce disproportionate platelet activation and adhesion. The complement system also stimulates thrombosis by inhibiting fibrinolysis and stimulating endothelial cells to release prothrombotic microparticles. These interactions see clinical relevance in several disorders where a deficiency in complement regulation seems to result in a prothrombotic clinical presentation. Finally, based on these observations, we present the outline of an observational cohort study that is currently under preparation and aimed at assessing how complement influences coagulation in patients with isolated TBI.

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Functional Relevance of the Anaphylatoxin Receptor C3aR for Platelet Function and Arterial Thrombus Formation Marks an Intersection Point Between Innate Immunity and Thrombosis

Abstract: Overall, our findings uncover a novel function of the anaphylatoxin C3a for platelet function and thrombus formation, highlighting a detrimental role of imbalanced complement activation in cardiovascular diseases.

Cited by 90 publications

References 58 publications

Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections

Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections

Quantifying single‐platelet biomechanics: An outsider’s guide to biophysical methods and recent advances

Does Complement-Mediated Hemostatic Disturbance Occur in Traumatic Brain Injury? A Literature Review and Observational Study Protocol

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