Neutrophils predominate the immune signature of cerebral thrombi in COVID-19 stroke patients

Genchi, Angela; Semerano, Aurora; Schwarz, Ghil; Dell’Acqua, Beatrice; Gullotta, Giorgia Serena; Sampaolo, Michela; Boeri, Enzo; Quattrini, Angelo; Sanvito, Francesca; Diamanti, Susanna; Bergamaschi, Andrea; Grassi, Sara; Podini, Paola; Panni, Pietro; Michelozzi, Caterina; Simionato, F.; Scomazzoni, Francesco; Remida, Paolo; Valvassori, Luca; Falini, Andrea; Ferrarese, Carlo; Michel, Patrik; Saliou, Guillaume; Hajdu, Steven D.; Beretta, Simone; Roveri, Luisa; Filippi, Massimo; Strambo, Davide; Martino, Gianvito; Bacigaluppi, Marco

doi:10.1186/s40478-022-01313-y

Cited by 35 publications

(33 citation statements)

References 48 publications

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“…Meanwhile, it was repeatedly shown that cerebral thrombi contain NETs ( 73 , 74 ) and it was speculated that mechanisms of immunothrombosis may be crucial in the pathophysiology of cryptogenic stroke. However, like in this work, the burden of NETs in thrombi of unclear origin did not substantially differ compared to clear stroke etiologies ( 75 , 76 ).…”

Section: Discussionsupporting

confidence: 67%

Insights Into Immunothrombotic Mechanisms in Acute Stroke due to Vaccine-Induced Immune Thrombotic Thrombocytopenia

et al. 2022

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During the COVID-19 pandemic, vaccination is the most important countermeasure. Pharmacovigilance concerns however emerged with very rare, but potentially disastrous thrombotic complications following vaccination with ChAdOx1. Platelet factor-4 antibody mediated vaccine-induced immune thrombotic thrombocytopenia (VITT) was described as an underlying mechanism of these thrombotic events. Recent work moreover suggests that mechanisms of immunothrombosis including neutrophil extracellular trap (NET) formation might be critical for thrombogenesis during VITT. In this study, we investigated blood and thrombus specimens of a female patient who suffered severe stroke due to VITT after vaccination with ChAdOx1 in comparison to 13 control stroke patients with similar clinical characteristics. We analyzed cerebral thrombi using histological examination, staining of complement factors, NET-markers, DNase and LL-37. In blood samples at the hyper-acute phase of stroke and 7 days later, we determined cell-free DNA, myeloperoxidase-histone complexes, DNase activity, myeloperoxidase activity, LL-37 and inflammatory cytokines. NET markers were identified in thrombi of all patients. Interestingly, the thrombus of the VITT-patient exclusively revealed complement factors and high amounts of DNase and LL-37. High DNase activity was also measured in blood, implying a disturbed NET-regulation. Furthermore, serum of the VITT-patient inhibited reactive oxygen species-dependent NET-release by phorbol-myristate-acetate to a lesser degree compared to controls, indicating either less efficient NET-inhibition or enhanced NET-induction in the blood of the VITT-patient. Additionally, the changes in specific cytokines over time were emphasized in the VITT-patient as well. In conclusion, insufficient resolution of NETs, e.g. by endogenous DNases or protection of NETs against degradation by embedded factors like the antimicrobial peptide LL-37 might thus be an important factor in the pathology of VITT besides increased NET-formation. On the basis of these findings, we discuss the potential implications of the mechanisms of disturbed NETs-degradation for diagnostic and therapeutic approaches in VITT-related thrombogenesis, other auto-immune disorders and beyond.

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Section: Discussionsupporting

confidence: 67%

Insights Into Immunothrombotic Mechanisms in Acute Stroke due to Vaccine-Induced Immune Thrombotic Thrombocytopenia

et al. 2022

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“…Microthrombi, rich in platelets, fibrin and granulocytes, were found in the vessels of lung, the kidneys, and the heart ( 163 ). Cerebral thrombi from COVID-19 patients with large vessel occlusion acute ischemic stroke show increased neutrophil infiltration ( 164 ). Curiously, despite an increase in neutrophils in the thrombi, no differences in the composition of thrombi, especially regarding NETs, between COVID-19 and control stroke patients were found ( 164 ), suggesting that neutrophils may induce immunothrombosis not exclusively via NET formation, or that other yet unidentified factors contribute to the thrombotic dysregulation.…”

Section: The Pathophysiological Influence Of Platelet-net Interplay I...mentioning

confidence: 99%

“…Cerebral thrombi from COVID-19 patients with large vessel occlusion acute ischemic stroke show increased neutrophil infiltration ( 164 ). Curiously, despite an increase in neutrophils in the thrombi, no differences in the composition of thrombi, especially regarding NETs, between COVID-19 and control stroke patients were found ( 164 ), suggesting that neutrophils may induce immunothrombosis not exclusively via NET formation, or that other yet unidentified factors contribute to the thrombotic dysregulation. Interestingly, LDGs, which are associated with autoimmune diseases and shown to cast NETs more frequently than “normal density” granulocytes, were found in COVID-19 patients ( 165 ).…”

Section: The Pathophysiological Influence Of Platelet-net Interplay I...mentioning

confidence: 99%

Platelets in the NETworks interweaving inflammation and thrombosis

2022

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Platelets are well characterized for their indispensable role in primary hemostasis to control hemorrhage. Research over the past years has provided a substantial body of evidence demonstrating that platelets also participate in host innate immunity. The surface expression of pattern recognition receptors, such as TLR2 and TLR4, provides platelets with the ability to sense bacterial products in their environment. Platelet α-granules contain microbicidal proteins, chemokines and growth factors, which upon release may directly engage pathogens and/or contribute to inflammatory signaling. Additionally, platelet interactions with neutrophils enhance neutrophil activation and are often crucial to induce a sufficient immune response. In particular, platelets can activate neutrophils to form neutrophil extracellular traps (NETs). This specific neutrophil effector function is characterized by neutrophils expelling chromatin fibres decorated with histones and antimicrobial proteins into the extracellular space where they serve to trap and kill pathogens. Until now, the mechanisms and signaling pathways between platelets and neutrophils inducing NET formation are still not fully characterized. NETs were also detected in thrombotic lesions in several disease backgrounds, pointing towards a role as an interface between neutrophils, platelets and thrombosis, also known as immunothrombosis. The negatively charged DNA within NETs provides a procoagulant surface, and in particular NET-derived proteins may directly activate platelets. In light of the current COVID-19 pandemic, the topic of immunothrombosis has become more relevant than ever, as a majority of COVID-19 patients display thrombi in the lung capillaries and other vascular beds. Furthermore, NETs can be found in the lung and other tissues and are associated with an increased mortality. Here, virus infiltration may lead to a cytokine storm that potently activates neutrophils and leads to massive neutrophil infiltration into the lung and NET formation. The resulting NETs presumably activate platelets and coagulation factors, further contributing to the subsequent emergence of microthrombi in pulmonary capillaries. In this review, we will discuss the interplay between platelets and NETs and the potential of this alliance to influence the course of inflammatory diseases. A better understanding of the underlying molecular mechanisms and the identification of treatment targets is of utmost importance to increase patients’ survival and improve the clinical outcome.

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“…This may be because basic diseases, such as hyperlipidemia and hyperglycemia, stimulate hematopoietic cells in the bone marrow to produce a large number of white blood cells in the circulating blood ( Stumvoll et al, 2005 ; Zhou et al, 2016 ; Vekic et al, 2019 ). Neutrophils are closely related to thrombosis in IS patients with COVID-19 ( Genchi et al, 2022 ). Neutrophils account for the majority of leukocytes in IS thrombi, followed by macrophages and T cells ( Heo et al, 2020 ).…”

Section: Pathogenesis Of Ischemic Strokementioning

confidence: 99%

Neuroprotective Effects of Quercetin on Ischemic Stroke: A Literature Review

Zhang

Yang

et al. 2022

Front. Pharmacol.

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Ischemic stroke (IS) is characterized by high recurrence and disability; however, its therapies are very limited. As one of the effective methods of treating acute attacks of IS, intravenous thrombolysis has a clear time window. Quercetin, a flavonoid widely found in vegetables and fruits, inhibits immune cells from secreting inflammatory cytokines, thereby reducing platelet aggregation and limiting inflammatory thrombosis. In pre-clinical studies, it has been shown to exhibit neuroprotective effects in patients with ischemic brain injury. However, its specific mechanism of action remains unknown. Therefore, this review aims to use published data to elucidate the potential value of quercetin in patients with ischemic brain injury. This article also reviews the plant sources, pharmacological effects, and metabolic processes of quercetin in vivo, thus focusing on its mechanism in inhibiting immune cell activation and inflammatory thrombosis as well as promoting neuroprotection against ischemic brain injury.

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Neutrophils predominate the immune signature of cerebral thrombi in COVID-19 stroke patients

Cited by 35 publications

References 48 publications

Insights Into Immunothrombotic Mechanisms in Acute Stroke due to Vaccine-Induced Immune Thrombotic Thrombocytopenia

Insights Into Immunothrombotic Mechanisms in Acute Stroke due to Vaccine-Induced Immune Thrombotic Thrombocytopenia

Platelets in the NETworks interweaving inflammation and thrombosis

Neuroprotective Effects of Quercetin on Ischemic Stroke: A Literature Review

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