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Article ; Online: Differential Effects of Erythropoietin Administration and Overexpression on Venous Thrombosis in Mice.

Stockhausen, Sven / Kilani, Badr / Schubert, Irene / Steinsiek, Anna-Lena / Chandraratne, Sue / Wendler, Franziska / Eivers, Luke / von Brühl, Marie-Luise / Massberg, Steffen / Ott, Ilka / Stark, Konstantin

Thrombosis and haemostasis

2023

Abstract: Background: Deep vein thrombosis (DVT) is a common condition associated with significant mortality due to pulmonary embolism. Despite advanced prevention and anticoagulation therapy, the incidence of venous thromboembolism remains unchanged. ... ...

Abstract	Background: Deep vein thrombosis (DVT) is a common condition associated with significant mortality due to pulmonary embolism. Despite advanced prevention and anticoagulation therapy, the incidence of venous thromboembolism remains unchanged. Individuals with elevated hematocrit and/or excessively high erythropoietin (EPO) serum levels are particularly susceptible to DVT formation. We investigated the influence of short-term EPO administration compared to chronic EPO overproduction on DVT development. Additionally, we examined the role of the spleen in this context and assessed its impact on thrombus composition. Methods: We induced ligation of the caudal vena cava (VCC) in EPO-overproducing Tg(EPO) mice as well as wildtype mice treated with EPO for two weeks, both with and without splenectomy. The effect on platelet circulation time was evaluated through FACS analysis, and thrombus composition was analyzed using immunohistology. Results: We present evidence for an elevated thrombogenic phenotype resulting from chronic EPO overproduction, achieved by combining an EPO-overexpressing mouse model with experimental DVT induction. This increased thrombotic state is largely independent of traditional contributors to DVT, such as neutrophils and platelets. Notably, the pronounced prothrombotic effect of red blood cells (RBCs) only manifests during chronic EPO overproduction and is not influenced by splenic RBC clearance, as demonstrated by splenectomy. In contrast, short-term EPO treatment does not induce thrombogenesis in mice. Consequently, our findings support the existence of a differential thrombogenic effect between chronic enhanced erythropoiesis and exogenous EPO administration. Conclusion: Chronic EPO overproduction significantly increases the risk of DVT, while short-term EPO treatment does not. These findings underscore the importance of considering EPO-related factors in DVT risk assessment and potential therapeutic strategies.
Language	English
Publishing date	2023-10-16
Publishing country	Germany
Document type	Journal Article
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1055/s-0043-1775965
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Article: Differential Effects of Erythropoietin Administration and Overexpression on Venous Thrombosis in Mice

Thrombosis and Haemostasis

2023

Abstract	Background: Deep vein thrombosis (DVT) is a common condition associated with significant mortality due to pulmonary embolism. Despite advanced prevention and anticoagulation therapy, the incidence of venous thromboembolism remains unchanged. Individuals with elevated hematocrit and/or excessively high erythropoietin (EPO) serum levels are particularly susceptible to DVT formation. We investigated the influence of short-term EPO administration compared to chronic EPO overproduction on DVT development. Additionally, we examined the role of the spleen in this context and assessed its impact on thrombus composition. Methods: We induced ligation of the caudal vena cava (VCC) in EPO-overproducing Tg(EPO) mice as well as wildtype mice treated with EPO for two weeks, both with and without splenectomy. The effect on platelet circulation time was evaluated through FACS analysis, and thrombus composition was analyzed using immunohistology. Results: We present evidence for an elevated thrombogenic phenotype resulting from chronic EPO overproduction, achieved by combining an EPO-overexpressing mouse model with experimental DVT induction. This increased thrombotic state is largely independent of traditional contributors to DVT, such as neutrophils and platelets. Notably, the pronounced prothrombotic effect of red blood cells (RBCs) only manifests during chronic EPO overproduction and is not influenced by splenic RBC clearance, as demonstrated by splenectomy. In contrast, short-term EPO treatment does not induce thrombogenesis in mice. Consequently, our findings support the existence of a differential thrombogenic effect between chronic enhanced erythropoiesis and exogenous EPO administration. Conclusion: Chronic EPO overproduction significantly increases the risk of DVT, while short-term EPO treatment does not. These findings underscore the importance of considering EPO-related factors in DVT risk assessment and potential therapeutic strategies.
Keywords	deep vein thrombosis ; red blood cells ; spleen ; erythropoietin ; sterile inflammation ; fibrin
Language	English
Publishing date	2023-10-16
Publisher	Georg Thieme Verlag KG
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1055/s-0043-1775965
Database	Thieme publisher's database

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Article ; Online: Peripheral priming induces plastic transcriptomic and proteomic responses in circulating neutrophils required for pathogen containment.

Kaiser, Rainer / Gold, Christoph / Joppich, Markus / Loew, Quentin / Akhalkatsi, Anastassia / Mueller, Tonina T / Offensperger, Felix / Droste Zu Senden, Augustin / Popp, Oliver / di Fina, Lea / Knottenberg, Viktoria / Martinez-Navarro, Alejandro / Eivers, Luke / Anjum, Afra / Escaig, Raphael / Bruns, Nils / Briem, Eva / Dewender, Robin / Muraly, Abhinaya /

Akgöl, Sezer / Ferraro, Bartolo / Hoeflinger, Jonathan K L / Polewka, Vivien / Khaled, Najib Ben / Allgeier, Julian / Tiedt, Steffen / Dichgans, Martin / Engelmann, Bernd / Enard, Wolfgang / Mertins, Philipp / Hubner, Norbert / Weckbach, Ludwig / Zimmer, Ralf / Massberg, Steffen / Stark, Konstantin / Nicolai, Leo / Pekayvaz, Kami

Science advances

2024 Volume 10, Issue 12, Page(s) eadl1710

Abstract: Neutrophils rapidly respond to inflammation and infection, but to which degree their functional trajectories after mobilization from the bone marrow are shaped within the circulation remains vague. Experimental limitations have so far hampered neutrophil ...

Abstract	Neutrophils rapidly respond to inflammation and infection, but to which degree their functional trajectories after mobilization from the bone marrow are shaped within the circulation remains vague. Experimental limitations have so far hampered neutrophil research in human disease. Here, using innovative fixation and single-cell-based toolsets, we profile human and murine neutrophil transcriptomes and proteomes during steady state and bacterial infection. We find that peripheral priming of circulating neutrophils leads to dynamic shifts dominated by conserved up-regulation of antimicrobial genes across neutrophil substates, facilitating pathogen containment. We show the TLR4/NF-κB signaling-dependent up-regulation of canonical neutrophil activation markers like CD177/NB-1 during acute inflammation, resulting in functional shifts in vivo. Blocking de novo RNA synthesis in circulating neutrophils abrogates these plastic shifts and prevents the adaptation of antibacterial neutrophil programs by up-regulation of distinct effector molecules upon infection. These data underline transcriptional plasticity as a relevant mechanism of functional neutrophil reprogramming during acute infection to foster bacterial containment within the circulation.
MeSH term(s)	Mice ; Humans ; Animals ; Neutrophils/metabolism ; Transcriptome ; Proteomics ; Inflammation/genetics ; Inflammation/metabolism ; Gene Expression Profiling
Language	English
Publishing date	2024-03-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adl1710
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Article: SpEDIT

Torres-Garcia, Sito / Di Pompeo, Lorenza / Eivers, Luke / Gaborieau, Baptiste / White, Sharon A / Pidoux, Alison L / Kanigowska, Paulina / Yaseen, Imtiyaz / Cai, Yizhi / Allshire, Robin C

Wellcome open research

2020 Volume 5, Page(s) 274

Abstract: The CRISPR/Cas9 system allows scarless, marker-free genome editing. Current CRISPR/Cas9 systems for the fission ... ...

Abstract	The CRISPR/Cas9 system allows scarless, marker-free genome editing. Current CRISPR/Cas9 systems for the fission yeast
Language	English
Publishing date	2020-11-24
Publishing country	England
Document type	Journal Article
ISSN	2398-502X
ISSN	2398-502X
DOI	10.12688/wellcomeopenres.16405.1
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Article ; Online: Thrombocytopenia and splenic platelet-directed immune responses after IV ChAdOx1 nCov-19 administration.

Nicolai, Leo / Leunig, Alexander / Pekayvaz, Kami / Esefeld, Max / Anjum, Afra / Rath, Justina / Riedlinger, Eva / Ehreiser, Vincent / Mader, Magdalena / Eivers, Luke / Hoffknecht, Marie-Louise / Zhang, Zhe / Kugelmann, Daniela / Rossaro, Dario / Escaig, Raphael / Kaiser, Rainer / Polewka, Vivien / Titova, Anna / Petzold, Tobias /

Spiekermann, Karsten / Iannacone, Matteo / Thiele, Thomas / Greinacher, Andreas / Stark, Konstantin / Massberg, Steffen

Blood

2022 Volume 140, Issue 5, Page(s) 478–490

Abstract: Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are based on a range of novel platforms, with adenovirus-based approaches (like ChAdOx1 nCov-19) being one of them. Recently, a novel complication of SARS-CoV-2-targeted ... ...

Abstract	Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are based on a range of novel platforms, with adenovirus-based approaches (like ChAdOx1 nCov-19) being one of them. Recently, a novel complication of SARS-CoV-2-targeted adenovirus vaccines has emerged: immune thrombocytopenia, either isolated, or accompanied by thrombosis (then termed VITT). This complication is characterized by low platelet counts, and in the case of VITT, also by platelet-activating platelet factor 4 antibodies reminiscent of heparin-induced thrombocytopenia, leading to a prothrombotic state with clot formation at unusual anatomic sites. Here, we detected antiplatelet antibodies targeting platelet glycoprotein receptors in 30% of patients with proven VITT (n = 27) and 42% of patients with isolated thrombocytopenia after ChAdOx1 nCov-19 vaccination (n = 26), indicating broad antiplatelet autoimmunity in these clinical entities. We use in vitro and in vivo models to characterize possible mechanisms of these platelet-targeted autoimmune responses leading to thrombocytopenia. We show that IV but not intramuscular injection of ChAdOx1 nCov-19 triggers platelet-adenovirus aggregate formation and platelet activation in mice. After IV injection, these aggregates are phagocytosed by macrophages in the spleen, and platelet remnants are found in the marginal zone and follicles. This is followed by a pronounced B-cell response with the emergence of circulating antibodies binding to platelets. Our work contributes to the understanding of platelet-associated complications after ChAdOx1 nCov-19 administration and highlights accidental IV injection as a potential mechanism of platelet-targeted autoimmunity. Hence, preventing IV injection when administering adenovirus-based vaccines could be a potential measure against platelet-associated pathologies after vaccination.
MeSH term(s)	Animals ; COVID-19/prevention & control ; COVID-19 Vaccines/adverse effects ; ChAdOx1 nCoV-19/adverse effects ; Immunity ; Mice ; Platelet Factor 4 ; SARS-CoV-2 ; Spleen ; Thrombocytopenia/etiology
Chemical Substances	COVID-19 Vaccines ; Platelet Factor 4 (37270-94-3) ; ChAdOx1 nCoV-19 (B5S3K2V0G8)
Language	English
Publishing date	2022-04-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2021014712
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Article ; Online: Mural cell-derived chemokines provide a protective niche to safeguard vascular macrophages and limit chronic inflammation.

Pekayvaz, Kami / Gold, Christoph / Hoseinpour, Parandis / Engel, Anouk / Martinez-Navarro, Alejandro / Eivers, Luke / Coletti, Raffaele / Joppich, Markus / Dionísio, Flávio / Kaiser, Rainer / Tomas, Lukas / Janjic, Aleksandar / Knott, Maximilian / Mehari, Fitsumbirhan / Polewka, Vivien / Kirschner, Megan / Boda, Annegret / Nicolai, Leo / Schulz, Heiko /

Titova, Anna / Kilani, Badr / Lorenz, Michael / Fingerle-Rowson, Günter / Bucala, Richard / Enard, Wolfgang / Zimmer, Ralf / Weber, Christian / Libby, Peter / Schulz, Christian / Massberg, Steffen / Stark, Konstantin

Immunity

2023 Volume 56, Issue 10, Page(s) 2325–2341.e15

Abstract: Maladaptive, non-resolving inflammation contributes to chronic inflammatory diseases such as atherosclerosis. Because macrophages remove necrotic cells, defective macrophage programs can promote chronic inflammation with persistent tissue injury. Here, ... ...

Abstract	Maladaptive, non-resolving inflammation contributes to chronic inflammatory diseases such as atherosclerosis. Because macrophages remove necrotic cells, defective macrophage programs can promote chronic inflammation with persistent tissue injury. Here, we investigated the mechanisms sustaining vascular macrophages. Intravital imaging revealed a spatiotemporal macrophage niche across vascular beds alongside mural cells (MCs)-pericytes and smooth muscle cells. Single-cell transcriptomics, co-culture, and genetic deletion experiments revealed MC-derived expression of the chemokines CCL2 and MIF, which actively preserved macrophage survival and their homeostatic functions. In atherosclerosis, this positioned macrophages in viable plaque areas, away from the necrotic core, and maintained a homeostatic macrophage phenotype. Disruption of this MC-macrophage unit via MC-specific deletion of these chemokines triggered detrimental macrophage relocalizing, exacerbated plaque necrosis, inflammation, and atheroprogression. In line, CCL2 inhibition at advanced stages of atherosclerosis showed detrimental effects. This work presents a MC-driven safeguard toward maintaining the homeostatic vascular macrophage niche.
MeSH term(s)	Humans ; Macrophages/metabolism ; Atherosclerosis/metabolism ; Plaque, Atherosclerotic/metabolism ; Chemokines/metabolism ; Inflammation/metabolism ; Necrosis/metabolism
Chemical Substances	Chemokines
Language	English
Publishing date	2023-08-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2023.08.002
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Article ; Online: Thrombocytopenia and splenic platelet directed immune responses after intravenous ChAdOx1 nCov-19 administration

Nicolai, Leo / Leunig, Alexander / Pekayvaz, Kami / Anjum, Afra / Riedlinger, Eva / Eivers, Luke / Hoffknecht, Marie-Louise / Rossaro, Dario / Escaig, Raphael / Kaiser, Rainer / Polewka, Vivien / Titova, Anna / Spiekermann, Karsten / Iannacone, Matteo / Stark, Konstantin / Massberg, Steffen

bioRxiv

Abstract: Vaccines against SARS-CoV-2 are based on a range of novel vaccine platforms, with adenovirus-based approaches (like ChAdOx1 nCov-19) being one of them. Recently a rare and novel complication of SARS-CoV-2 targeted adenovirus vaccines has emerged: ... ...

Abstract	Vaccines against SARS-CoV-2 are based on a range of novel vaccine platforms, with adenovirus-based approaches (like ChAdOx1 nCov-19) being one of them. Recently a rare and novel complication of SARS-CoV-2 targeted adenovirus vaccines has emerged: thrombosis with thrombocytopenia syndrome (TTS). TTS is characterized by low platelet counts, clot formation at unusual anatomic sites and platelet-activating PF4-polyanion antibodies reminiscent of heparin-induced thrombocytopenia. Here, we employ in vitro and in vivo models to characterize the possible mechanisms of this platelet-targeted autoimmunity. We show that intravenous but not intramuscular injection of ChAdOx1 nCov-19 triggers platelet-adenovirus aggregate formation and platelet activation. After intravenous injection, these aggregates are phagocytosed by macrophages in the spleen and platelet remnants are found in the marginal zone and follicles. This is followed by a pronounced B-cell response with the emergence of circulating antibodies binding to platelets. Our work contributes to the understanding of TTS and highlights accidental intravenous injection as potential mechanism for post-vaccination TTS. Hence, safe intramuscular injection, with aspiration prior to injection, could be a potential preventive measure when administering adenovirus-based vaccines.
Keywords	covid19
Language	English
Publishing date	2021-06-29
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.06.29.450356
Database	COVID19

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Article ; Online: Protective immune trajectories in early viral containment of non-pneumonic SARS-CoV-2 infection.

Pekayvaz, Kami / Leunig, Alexander / Kaiser, Rainer / Joppich, Markus / Brambs, Sophia / Janjic, Aleksandar / Popp, Oliver / Nixdorf, Daniel / Fumagalli, Valeria / Schmidt, Nora / Polewka, Vivien / Anjum, Afra / Knottenberg, Viktoria / Eivers, Luke / Wange, Lucas E / Gold, Christoph / Kirchner, Marieluise / Muenchhoff, Maximilian / Hellmuth, Johannes C /

Scherer, Clemens / Rubio-Acero, Raquel / Eser, Tabea / Deák, Flora / Puchinger, Kerstin / Kuhl, Niklas / Linder, Andreas / Saar, Kathrin / Tomas, Lukas / Schulz, Christian / Wieser, Andreas / Enard, Wolfgang / Kroidl, Inge / Geldmacher, Christof / von Bergwelt-Baildon, Michael / Keppler, Oliver T / Munschauer, Mathias / Iannacone, Matteo / Zimmer, Ralf / Mertins, Philipp / Hubner, Norbert / Hoelscher, Michael / Massberg, Steffen / Stark, Konstantin / Nicolai, Leo

Nature communications

2022 Volume 13, Issue 1, Page(s) 1018

Abstract: The antiviral immune response to SARS-CoV-2 infection can limit viral spread and prevent development of pneumonic COVID-19. However, the protective immunological response associated with successful viral containment in the upper airways remains unclear. ... ...

Abstract	The antiviral immune response to SARS-CoV-2 infection can limit viral spread and prevent development of pneumonic COVID-19. However, the protective immunological response associated with successful viral containment in the upper airways remains unclear. Here, we combine a multi-omics approach with longitudinal sampling to reveal temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients and associate specific immune trajectories with upper airway viral containment. We see a distinct systemic rather than local immune state associated with viral containment, characterized by interferon stimulated gene (ISG) upregulation across circulating immune cell subsets in non-pneumonic SARS-CoV2 infection. We report reduced cytotoxic potential of Natural Killer (NK) and T cells, and an immune-modulatory monocyte phenotype associated with protective immunity in COVID-19. Together, we show protective immune trajectories in SARS-CoV2 infection, which have important implications for patient prognosis and the development of immunomodulatory therapies.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Ambulatory Care ; COVID-19/immunology ; Cytokines/blood ; Female ; Gene Expression Regulation ; Gene Regulatory Networks ; Humans ; Interferons/immunology ; Killer Cells, Natural/immunology ; Longitudinal Studies ; Male ; Middle Aged ; Monocytes/immunology ; Nasopharynx/immunology ; Nasopharynx/virology ; SARS-CoV-2/physiology ; T-Lymphocytes/immunology
Chemical Substances	Cytokines ; Interferons (9008-11-1)
Language	English
Publishing date	2022-02-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-28508-0
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