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OBJECTIVE: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with limited therapeutic options. KRAS mutations are among the most abundant genetic alterations in iCCA associated with poor clinical outcome and treatment response. Recent findings indicate that Poly(ADP-ribose)polymerase1 (PARP-1) is implicated in KRAS-driven cancers, but its exact role in cholangiocarcinogenesis remains undefined. DESIGN: PARP-1 inhibition was performed in patient-derived and established iCCA cells using RNAi, CRISPR/Cas9 and pharmacological inhibition in KRAS-mutant, non-mutant cells. In addition, Parp-1 knockout mice were combined with iCCA induction by hydrodynamic tail vein injection to evaluate an impact on phenotypic and molecular features of Kras-driven and Kras-wildtype iCCA. Clinical implications were confirmed in authentic human iCCA. RESULTS: PARP-1 was significantly enhanced in KRAS-mutant human iCCA. PARP-1-based interventions preferentially impaired cell viability and tumourigenicity in human KRAS-mutant cell lines. Consistently, loss of Parp-1 provoked distinct phenotype in Kras/Tp53-induced versus Akt/Nicd-induced iCCA and abolished Kras-dependent cholangiocarcinogenesis. Transcriptome analyses confirmed preferential impairment of DNA damage response pathways and replicative stress response mediated by CHK1. Consistently, inhibition of CHK1 effectively reversed PARP-1 mediated effects. Finally, Parp-1 depletion induced molecular switch of KRAS-mutant iCCA recapitulating good prognostic human iCCA patients. CONCLUSION: Our findings identify the novel prognostic and therapeutic role of PARP-1 in iCCA patients with activation of oncogenic KRAS signalling.
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BACKGROUND: Cardiogenic shock (CS) is characterized by high mortality and requires accurate prognostic tools to predict outcomes and guide treatment. The Society for Cardiovascular Angiography and Interventions (SCAI) shock classification indicates shock severity and can be used for outcome prediction. OBJECTIVE: Here, we compare the prognostic performance of SCAI shock classification determined on admission and during intensive care unit (ICU) stay. METHODS: We included all patients with CS or conditions associated with developing CS based on ICD codes. SCAI shock stages were determined on admission and during the first 5 days of ICU stay. Receiver operating curves were used to compare the prognostic performance of SCAI stages on admission, SCAI stages during ICU stay and CS evolution (absent, resolved, persistent and new onset) for in-hospital mortality. RESULTS: Between 01/2018 and 06/2022, 1303 patients were identified and 862 patients were included. On admission, 50.6 % patients had SCAI shock stage A, 3.9 % SCAI shock stage B, 17.7 % SCAI shock stage C, 7.0 % SCAI shock stage D and 20.8 % SCAI shock stage E. Shock stage distribution changed dynamically during ICU stay. Compared to SCAI stage on admission (AUC 0.80; 95 % CI 0.77-0.83), highest achieved SCAI stage during ICU (AUC 0.86, 95 % CI 0.83-0.89, p < 0.0001) and shock evolution (AUC 0.87, 95 % CI 0.85-0.90, p < 0.0001) yielded better prognostic performance. CONCLUSIONS: SCAI shock stages changed dynamically during ICU stay, and prognostic performance can be improved by considering highest achieved SCAI shock stage as well as the evolution of CS compared to SCAI shock stage on admission.
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AIM: Data on associations of invasively determined hemodynamic parameters with procedural success and outcomes in patients suffering from mitral regurgitation (MR) undergoing transcatheter edge-to-edge repair of the mitral valve (M-TEER) is limited. METHODS AND RESULTS: We enrolled 239 patients with symptomatic MR of grade 2 + , who received M-TEER. All patients underwent extensive pre-interventional invasive hemodynamic measurements via right heart catheterization (mean pulmonary arterial pressure (mPAP), systolic- (PAPsys) and diastolic pulmonary arterial pressure (PAPdia), pulmonary arterial wedge pressure (PAWP), a-wave, v-wave, pulmonary vascular resistance (PVR), transpulmonary pressure gradient (TPG), cardiac index (CI), stroke volume index (SVI)). mPAP and PAWP at baseline were neither associated with procedural success, immediate reduction of MR, nor residual MR after 6 months of follow-up. The composite outcome (All-cause mortality (ACM) and/or heart failure induced rehospitalization (HFH)) and HFH differed significantly after M-TEER when stratified according to mPAP, PAWP, PAPdia, a-wave and v-wave. ACM was not associated with the afore mentioned parameters. Neither PVR, TPG, CI nor SVI were associated with the composite outcome and HFH, respectively. In multivariable analyses, PAWP was independently associated with the composite outcome and HFH. PVR and SVI were not associated with outcomes. CONCLUSION: PAWP at baseline was significantly and independently associated with HFH and might serve as a valuable parameter for identifying patients at high risk for HFH after M-TEER. ACM and procedural success were not affected by pulmonary arterial pressure before M-TEER. We suggest that the post-capillary component of PH serves as the driving force behind the risk of HFH.
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Atherosclerosis, a major contributor to cardiovascular morbidity and mortality, is characterized by chronic inflammation of the arterial wall. This inflammatory process is initiated and maintained by both innate and adaptive immunity. Dendritic cells (DCs), which are antigen-presenting cells, play a crucial role in the development of atherosclerosis and consist of various subtypes with distinct functional abilities. Following the recognition and binding of antigens, DCs become potent activators of cellular responses, bridging the innate and adaptive immune systems. The modulation of specific DC subpopulations can have either pro-atherogenic or atheroprotective effects, highlighting the dual pro-inflammatory or tolerogenic roles of DCs. In this work, we provide a comprehensive overview of the evolving roles of DCs and their subtypes in the promotion or limitation of atherosclerosis development. Additionally, we explore antigen pulsing and pharmacological approaches to modulate the function of DCs in the context of atherosclerosis.
Subject(s)
Atherosclerosis , Dendritic Cells , Humans , Atherosclerosis/metabolism , Adaptive Immunity , Inflammation/metabolismABSTRACT
BACKGROUND: Cardiac resynchronisation therapy (CRT) can be necessary in patients with chronic heart failure, who have already been provided with transvenous cardiac implantable electrical devices. Upgrade procedures revealed controversial results, while long-term outcomes regarding underlying Ischaemic- (ICM) or Non-Ischaemic heart disease (NICM) have yet to be described. METHODS: The Mannheim Cardiac Resynchronisation Therapy Registry (MARACANA) was designed as a retrospective observational single-centre registry, including all CRT implantations from 2013-2021 (n = 459). CRT upgrades (n = 136) were retrospectively grouped to either ICM (n = 84) or NICM (n = 52) and compared for New York Heart Association classification (NYHA), paced QRS-width, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE) and other heart failure modification aspects in the long-term (59.3 ± 5 months). RESULTS: Baseline-characteristics including paced QRS-width, upgrade indications or NYHA-classification were comparable for both groups (group comparison p>.05). The CRT upgrade improved NYHA (ICM: 2.98 ± 0.4 to 2.29 ± 0.7, NICM: 2.94 ± 0.5 to 2.08 ± 0.5) and the LVEF (ICM: 27.2 ± 6.6 to 38.25 ± 8.8, NICM: 30.2 ± 9.4 to 38.7 ± 13.8%) after five years, irrespective of underlying heart disease (each group p < .05, group comparison p>.05). Only ICM revealed significant improvements in TAPSE (15.9 ± 4.1 to 18.9 ± 4.1 mm) and narrowing of the paced QRS-width (185.4 ± 29 to 147.2 ± 16.3 ms) after five years (each p < .05). CONCLUSIONS: Upgrade to CRT might improve heart failure symptoms and left-ventricular systolic function in the long-term, irrespective of underlying ischaemic or non-ischaemic heart disease.
ABSTRACT
Pathogen-associated molecular patterns (PAMPs) are involved in the pathogenesis of septic cardiomyopathy through a toll-like receptor (TLR)-mediated immune response. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can reflect the innate immune abilities of cardiomyocytes. Therefore, hiPSC-CMs may provide an attractive tool with which to study PAMP-induced alterations in cardiomyocytes. HiPSC-CMs from two different healthy donors were exposed to the PAMP flagellin (FLA) at different doses and exposure times. Alterations in the expression levels of distinct inflammation-associated cytokines, intracellular inflammation pathways including TLR5 downstream signaling, reactive oxygen species levels and surface antigen composition were assessed using PCR, ELISA and FACS techniques. Higher doses of flagellin increased the expression levels of inflammation-associated cytokines like TNFα (p < 0.01) and downstream signaling molecules like caspase-8 (p < 0.05). TLR5 expression (p < 0.01) and TLR5 fluorescence proportion (p < 0.05) increased in hiPSC-CMs after prolonged FLA exposure. FLA-induced innate immune response processes in cardiomyocytes might be detectable with an hiPSC-CMs-based in vitro model.
Subject(s)
Flagellin , Induced Pluripotent Stem Cells , Humans , Flagellin/pharmacology , Myocytes, Cardiac , Toll-Like Receptor 5/genetics , Immunity, Innate , Cytokines , InflammationABSTRACT
Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases.
Subject(s)
Fibroblast Growth Factor 2 , Vascular Endothelial Growth Factor B , Humans , Fibroblast Growth Factor 2/genetics , Immunotherapy , Receptor, Fibroblast Growth Factor, Type 1/geneticsABSTRACT
Importance: The Global Registry of Acute Coronary Events (GRACE) risk score, a guideline-recommended risk stratification tool for patients presenting with acute coronary syndromes (ACS), does not consider the extent of myocardial injury. Objective: To assess the incremental predictive value of a modified GRACE score incorporating high-sensitivity cardiac troponin (hs-cTn) T at presentation, a surrogate of the extent of myocardial injury. Design, Setting, and Participants: This retrospectively designed longitudinal cohort study examined 3 independent cohorts of 9803 patients with ACS enrolled from September 2009 to December 2017; 2 ACS derivation cohorts (Heidelberg ACS cohort and Newcastle STEMI cohort) and an ACS validation cohort (SPUM-ACS study). The Heidelberg ACS cohort included 2535 and the SPUM-ACS study 4288 consecutive patients presenting with a working diagnosis of ACS. The Newcastle STEMI cohort included 2980 consecutive patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Data were analyzed from March to June 2023. Exposures: In-hospital, 30-day, and 1-year mortality risk estimates derived from an updated risk score that incorporates continuous hs-cTn T at presentation (modified GRACE). Main Outcomes and Measures: The predictive value of continuous hs-cTn T and modified GRACE risk score compared with the original GRACE risk score. Study end points were all-cause mortality during hospitalization and at 30 days and 1 year after the index event. Results: Of 9450 included patients, 7313 (77.4%) were male, and the mean (SD) age at presentation was 64.2 (12.6) years. Using continuous rather than binary hs-cTn T conferred improved discrimination and reclassification compared with the original GRACE score (in-hospital mortality: area under the receiver operating characteristic curve [AUC], 0.835 vs 0.741; continuous net reclassification improvement [NRI], 0.208; 30-day mortality: AUC, 0.828 vs 0.740; NRI, 0.312; 1-year mortality: AUC, 0.785 vs 0.778; NRI, 0.078) in the derivation cohort. These findings were confirmed in the validation cohort. In the pooled population of 9450 patients, modified GRACE risk score showed superior performance compared with the original GRACE risk score in terms of reclassification and discrimination for in-hospital mortality end point (AUC, 0.878 vs 0.780; NRI, 0.097), 30-day mortality end point (AUC, 0.858 vs 0.771; NRI, 0.08), and 1-year mortality end point (AUC, 0.813 vs 0.797; NRI, 0.056). Conclusions and Relevance: In this study, using continuous rather than binary hs-cTn T at presentation, a proxy of the extent of myocardial injury, in the GRACE risk score improved the mortality risk prediction in patients with ACS.
Subject(s)
Acute Coronary Syndrome , Risk Assessment , ST Elevation Myocardial Infarction , Troponin T , Female , Humans , Male , Middle Aged , Acute Coronary Syndrome/blood , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/mortality , Acute Coronary Syndrome/therapy , Longitudinal Studies , Registries , Retrospective Studies , Risk Factors , ST Elevation Myocardial Infarction/blood , ST Elevation Myocardial Infarction/diagnosis , Troponin T/blood , AgedABSTRACT
Background and aims: Preclinical data suggest that activation of the adaptive immune system is critical for myocardial repair processes in acute myocardial infarction. The aim of the present study was to determine the clinical value of baseline effector T cell chemokine IP-10 blood levels in the acute phase of ST-segment elevation myocardial infarction (STEMI) for the prediction of the left ventricular function changes and cardiovascular outcomes after STEMI. Methods: Serum IP-10 levels were retrospectively quantified in two independent cohorts of STEMI patients undergoing primary percutaneous coronary intervention. Results: We report a biphasic response of the effector T cell trafficking chemokine IP-10 characterized by an initial increase of its serum levels in the acute phase of STEMI followed by a rapid reduction at 90min post reperfusion. Patients at the highest IP-10 tertile presented also with more CD4 effector memory T cells (CD4 TEM cells), but not other T cell subtypes, in blood. In the Newcastle cohort (n=47), patients in the highest IP-10 tertile or CD4 TEM cells at admission exhibited an improved cardiac systolic function 12 weeks after STEMI compared to patients in the lowest IP-10 tertile. In the Heidelberg cohort (n=331), STEMI patients were followed for a median of 540 days for major adverse cardiovascular events (MACE). Patients presenting with higher serum IP-10 levels at admission had a lower risk for MACE after adjustment for traditional risk factors, CRP and high-sensitivity troponin-T levels (highest vs. rest quarters: HR [95% CI]=0.420 [0.218-0.808]). Conclusion: Increased serum levels of IP-10 in the acute phase of STEMI predict a better recovery in cardiac systolic function and less adverse events in patients after STEMI.
Subject(s)
Myocardial Infarction , ST Elevation Myocardial Infarction , Humans , Chemokine CXCL10 , Heart , Retrospective Studies , ST Elevation Myocardial Infarction/therapyABSTRACT
In ischemic tissue, platelets can modulate angiogenesis. The specific factors influencing this function, however, are poorly understood. Here, we characterized the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) expressed on platelets as a potent regulator of ischemia-driven revascularization. We assessed the relevance of the anaphylatoxin receptor C5aR1 on platelets in patients with coronary artery disease as well as those with peripheral artery disease and used genetic mouse models to characterize its significance for ischemia and growth factor-driven revascularization. The presence of C5aR1-expressing platelets was increased in the hindlimb ischemia model. Ischemia-driven angiogenesis was significantly improved in C5aR1-/- mice but not in C5-/- mice, suggesting a specific role of C5aR1. Experiments using the supernatant of C5a-stimulated platelets suggested a paracrine mechanism of angiogenesis inhibition by platelets by means of antiangiogenic CXC chemokine ligand 4 (CXCL4, PF4). Lineage-specific C5aR1 deletion verified that the secretion of CXCL4 depends on C5aR1 ligation on platelets. Using C5aR1-/-CXCL4-/- mice, we observed no additional effect in the revascularization response, underscoring a strong dependence of CXCL4 secretion on the C5a-C5aR1-axis. We identified a novel mechanism for inhibition of neovascularization via platelet C5aR1, which was mediated by the release of antiangiogenic CXCL4.
Subject(s)
Anaphylatoxins , Intercellular Signaling Peptides and Proteins , Humans , Mice , Animals , Ischemia/etiology , Receptor, Anaphylatoxin C5aABSTRACT
Platelets are important cellular targets in cardiovascular disease. Based on insights from basic science, translational approaches and clinical studies, a distinguished anti-platelet drug treatment regimen for cardiovascular patients could be established. Furthermore, platelets are increasingly considered as cells mediating effects "beyond thrombosis", including vascular inflammation, tissue remodeling and healing of vascular and tissue lesions. This review has its focus on the functions and interactions of platelets with potential translational and clinical relevance. The role of platelets for the development of atherosclerosis and therapeutic modalities for primary and secondary prevention of atherosclerotic disease are addressed. Furthermore, novel therapeutic options for inhibiting platelet function and the use of platelets in regenerative medicine are considered.
Subject(s)
Atherosclerosis , Cardiovascular Diseases , Myocardial Infarction , Thrombosis , Humans , Cardiovascular Diseases/drug therapy , Blood Platelets , Atherosclerosis/drug therapy , Atherosclerosis/pathology , Thrombosis/drug therapy , Myocardial Infarction/drug therapyABSTRACT
Background: Percutaneous mitral valve repair (PMVR) has evolved to be a standard procedure in suitable patients with mitral regurgitation (MR) not accessible for open surgery. Here, we analyzed the influence of the number and positioning of the clips implanted during the procedure on MR reduction analyzing also sub-collectives of functional and degenerative MR (DMR). Results: We included 410 patients with severe MR undergoing PMVR using the MitraClip® System. MR and reduction of MR were analyzed by TEE at the beginning and at the end of the PMVR procedure. To specify the clip localization, we sub-divided segment 2 into 3 sub-segments using the segmental classification of the mitral valve. Results: We found an enhanced reduction of MR predominantly in DMR patients who received more than one clip. Implantation of only one clip led to a higher MR reduction in patients with functional MR (FMR) in comparison to patients with DMR. No significant differences concerning pressure gradients could be observed in degenerative MR patients regardless of the number of clips implanted. A deterioration of half a grade of the achieved MR reduction was observed 6 months post-PMVR independent of the number of implanted clips with a better stability in FMR patients, who got 3 clips compared to patients with only one clip. Conclusions: In patients with FMR, after 6 months the reduction of MR was more stable with an increased number of implanted clips, which suggests that this specific patient collective may benefit from a higher number of clips.
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Different types of immune cells are involved in atherogenesis and may act atheroprotective or atheroprogressive. Here, we describe an in vitro approach to analyze CD11c+ cells and CD11c+-derived ApoE in atherosclerosis. The major steps include harvesting mouse bone marrow, plating cells in culture dishes, treating them with differentiation factors, and collecting cells after removal of undesirable populations. This protocol can be adapted for CD11c+ cells in different contexts, thus, serving as models for different diseases and to analyze cell-specific molecules. For complete details on the use and execution of this protocol, please refer to Sauter et al. (2021).
Subject(s)
Bone Marrow , Dendritic Cells , Animals , Apolipoproteins E , Bone Marrow Cells , CD11c Antigen , MiceABSTRACT
Platelets are key mediators of thrombus formation and inflammation during the acute phase of ischaemic stroke. Particularly, the platelet glycoprotein (GP) receptors GPIbα and GPVI have been shown to mediate platelet adhesion and activation in the ischaemic brain. GPIbα and GPVI blockade could reduce infarct volumes and improve functional outcome in mouse models of acute ischaemic stroke, without concomitantly increasing intracerebral haemorrhage. However, the functional role of platelets during long-term stroke recovery has not been elucidated so far. Thus, we here examined the impact of platelet depletion on post-stroke recovery after transient middle cerebral artery occlusion (tMCAO) in adult male mice. Platelet depleting antibodies or isotype control were applied from day 3-28 after tMCAO in mice matched for infarct size. Long-term functional recovery was assessed over the course of 28 days by behavioural testing encompassing motor and sensorimotorical functions, as well as anxiety-like or spontaneous behaviour. Whole brain flow cytometry and light sheet fluorescent microscopy were used to identify resident and infiltrated immune cell types, and to determine the effects of platelet depletion on the cerebral vascular architecture, respectively. We found that delayed platelet depletion does not improve long-term functional outcome in the tMCAO stroke model. Immune cell abundance, the extent of thrombosis and the organisation of the cerebral vasculature were also comparable between platelet-depleted and control mice. Our study demonstrates that, despite their critical role in the acute stroke setting, platelets appear to contribute only marginally to tissue reorganisation and functional recovery at later stroke stages.
ABSTRACT
Here, we describe an in vivo approach to visualize CD11c+ cells in atherosclerosis. In particular, we use a protocol for X-Gal staining of immune cells within atherosclerotic plaques, which can be used as an alternative to analyze plaque composition and cell-specific molecules in atherogenesis. LacZ knockin mice have to be bred to mice carrying the CD11ccre recombinase-both brought onto an ApoE-/- background-to be able to visualize this cell type of interest in the plaques by X-Gal staining. With this approach, different immune cells in atherogenesis can be examined. For complete details on the use and execution of this protocol, please refer to Sauter et al. (2021).
Subject(s)
Atherosclerosis , Plaque, Atherosclerotic , Animals , Atherosclerosis/genetics , CD11c Antigen/genetics , Lac Operon/genetics , Mice , Mice, Knockout , Plaque, Atherosclerotic/geneticsABSTRACT
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.
Subject(s)
Blood Platelets , Thrombosis , Adenosine Triphosphate/metabolism , Blood Platelets/metabolism , Humans , Inflammation/metabolism , Nociception , Pain/metabolism , Receptors, Purinergic P2X/metabolism , Receptors, Purinergic P2X7/metabolism , Thromboinflammation , Thrombosis/metabolismABSTRACT
Genetic predisposition through F11R-single-nucleotide variation (SNV) influences circulatory soluble junctional adhesion molecule-A (sJAM-A) levels in coronary artery disease (CAD) patients. Homozygous carriers of the minor alleles (F11R-SNVs rs2774276, rs790056) show enhanced levels of thrombo-inflammatory sJAM-A. Both F11R-SNVs and sJAM-A are associated with worse prognosis for recurrent myocardial infarction in CAD patients. Platelet surface-associated JAM-A correlate with platelet activation markers in CAD patients. Activated platelets shed transmembrane-JAM-A, generating proinflammatory sJAM-A and JAM-A-bearing microparticles. Platelet transmembrane-JAM-A and sJAM-A as homophilic interaction partners exaggerate thrombotic and thrombo-inflammatory platelet monocyte interactions. Therapeutic strategies interfering with this homophilic interface may regulate thrombotic and thrombo-inflammatory platelet response in cardiovascular pathologies where circulatory sJAM-A levels are elevated.
ABSTRACT
Platelet activation plays a critical role in thrombosis. Inhibition of platelet activation is a cornerstone in treatment of acute organ ischemia. Platelet ACKR3 surface expression is independently associated with all-cause mortality in CAD patients. In a novel genetic mouse strain, we show that megakaryocyte/platelet-specific deletion of ACKR3 results in enhanced platelet activation and thrombosis in vitro and in vivo. Further, we performed ischemia/reperfusion experiments (transient LAD-ligation and tMCAO) in mice to assess the impact of genetic ACKR3 deficiency in platelets on tissue injury in ischemic myocardium and brain. Loss of platelet ACKR3 enhances tissue injury in ischemic myocardium and brain and aggravates tissue inflammation. Activation of platelet-ACKR3 via specific ACKR3 agonists inhibits platelet activation and thrombus formation and attenuates tissue injury in ischemic myocardium and brain. Here we demonstrate that ACKR3 is a critical regulator of platelet activation, thrombus formation and organ injury following ischemia/reperfusion.