Stroke and myocardial infarction induce neutrophil extracellular trap release disrupting lymphoid organ structure and immunoglobulin secretion

Tuz, Ali A.; Ghosh, Susmita; Karsch, Laura; Ttoouli, Dimitris; Sata, Sai P.; Ulusoy, Özgür; Kraus, Andreas; Hoerenbaum, Nils; Wolf, Jan-Niklas; Lohmann, Sabrina; Zwirnlein, Franziska; Kaygusuz, Viola; Lakovic, Vivian; Tummes, Hannah-Lea; Beer, Alexander; Gallert, Markus; Thiebes, Stephanie; Qefalia, Altea; Cibir, Zülal; Antler, Medina; Korste, Sebastian; Haj Yehia, Elias; Michel, Lars; Rassaf, Tienush; Kaltwasser, Britta; Abdelrahman, Hossam; Mohamud Yusuf, Ayan; Wang, Chen; Yin, Dongpei; Haeusler, Lars; Lueong, Smiths; Richter, Mathis; Engel, Daniel R.; Stenzel, Martin; Soehnlein, Oliver; Frank, Benedikt; Solo-Nomenjanahary, Mialitiana; Ho-Tin-Noé, Benoît; Siveke, Jens T.; Totzeck, Matthias; Hoffmann, Daniel; Grüneboom, Anika; Hagemann, Nina; Hasenberg, Anja; Desilles, Jean-Philippe; Mazighi, Mikael; Sickmann, Albert; Chen, Jianxu; Hermann, Dirk M.; Gunzer, Matthias; Singh, Vikramjeet

doi:10.1038/s44161-024-00462-8

Cited by 7 publications

(2 citation statements)

References 48 publications

(55 reference statements)

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Section: Discussionsupporting

confidence: 58%

“…In this present work, we show that DNase-fragmented NETs, but not intact NETs, directly potentiate T cell activation. In line with these results, a report showed that DNase treatment can prevent the reduction of T cell accumulation in lymphoid organs of ischemically injured mice [80]. Furthermore, DNase treatment or intratracheal administration of DNase-fragmented NETs were found to induce the activation of naive CD4 T cells adoptively transferred into lung allograft recipients, as well as to stimulate intragraft effector T cell accumulation [13].…”

Section: Discussionmentioning

confidence: 80%

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Differential action modes of Neutrophil Extracellular Trap-targeted drugs define T cell responses in SARS-CoV-2 infection

Bonilha,

Veras,

Ramos

et al. 2024

Preprint

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Neutrophil extracellular traps (NETs) play a dual role in SARS-CoV-2 infection, aiding early immune defense but also contributing to lung damage. While NET targeting may improve clinical outcomes in SARS-CoV-2 infection, its impact on adaptive immunity, crucial for fighting the virus, remains unclear. Our study demonstrates that both recombinant human DNase (rhDNase), degrading NET structure, and GSK484, inhibiting NET formation, reduce lung NET concentration and improve clinical outcomes in infected mice, yet they differ in their influence on T cell responses. We show that rhDNase does not impact T cell responses, whereas GSK484 diminishes virus-specific T cell responses.In vitro, GSK484 decreases dendritic cell antigen presentation by impairing antigen uptake and reduces IL-2 signaling by affecting its production by T cells. In a model of lung inflammation, GSK484 diminishes antigen-specific T cell activation and proliferation, while rhDNase shows a potential to boost T cell responses via the presence of NET fragments that reduce T cell activation threshold. Our findings suggest that NET targeting with rhDNase or GSK484 holds therapeutic potential for treating SARS-CoV-2 infection, while their distinct modes of action shape T cell responses during the infection.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 80%

Differential action modes of Neutrophil Extracellular Trap-targeted drugs define T cell responses in SARS-CoV-2 infection

Bonilha,

Veras,

Ramos

et al. 2024

Preprint

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Proteomic Characterization of 1000 Human and Murine Neutrophils Freshly Isolated From Blood and Sites of Sterile Inflammation

Ghosh,

Tuz,

Stenzel

et al. 2024

Molecular & Cellular Proteomics

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Delayed DNase-I Administration but Not Gasdermin-D Inhibition Induces Hemorrhagic Transformation After Transient Focal Cerebral Ischemia in Mice

Yin,

Wang,

Singh

et al. 2024

Stroke

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olymorphonuclear neutrophils are early invaders of the ischemic brain and exacerbate brain damage. 1,2 Neutrophil-released extracellular DNA traps significantly contribute to ischemic damage. 3 Hence, 3 randomized controlled trials currently assess the effects of intravenously administered DNase-I, which degrades neutrophil-released extracellular DNA traps, in patients with stroke (URL: https://www.clinicaltrials. gov; Unique identifier: NCT05203224, NCT05880524, NCT04785066). To explore the roles of neutrophilreleased extracellular DNA traps, we exposed 10-to 12-week-old male C57BL6/j mice (Envigo, Darmstadt, Germany) anesthetized with 1.5% isoflurane (30% O 2 , remainder N 2 O) to 30 minutes intraluminal middle cerebral artery occlusion (MCAO). 3 Rectal temperature was maintained at 37 °C. Laser Doppler flow was recorded above the middle cerebral artery territory. Buprenorphine (0.1 mg/kg SC; Reckitt Benckiser, Slough, United Kingdom) was injected before MCAO for analgesia, followed by carprofen (4 mg/kg per day SC; Bayer, Leverkusen, Germany) at 0, 24, and 48 hours post-MCAO as anti-inflammatory drug. Immediately or 72 hours post-MCAO, vehicle or DNase-I (10 µg; 11284932001; Roche, Basel, Switzerland) was IV administered. In the high-dose, but not low-dose group, vehicle or DNase-I (50 µg) was simultaneously applied IP. This IP DNase-I administration was repeated 3× at 12-hour intervals in the high-dose group. In groups with immediate highdose DNase-I delivery, vehicle or recombinant tPA ([tissue-type plasminogen activator]; 10 mg/kg IV, 10% as bolus, 90% as 30-minute infusion; Actilyse, Boehringer-Ingelheim, Ingelheim, Germany) was administered 10 minutes after DNase-I. In additional studies, vehicle or the gasdermin-D inhibitor LDC7559 (10 mg/ kg IP; HY-111674; MedChemExpress, Monmouth Junction, NJ), which prevents neutrophil extracellular DNA trap release, 3 was injected at 72 hours post-MCAO. At 120 hours post-MCAO, mice were deeply anesthetized and transcardially perfused with PBS, followed by 4% paraformaldehyde. From 20-µm-thick brain sections collected at 1-mm intervals, cresyl violet stainings were performed, which were analyzed with ImageJ (National Institutes of Health, Bethesda, MD). Infarct volume was measured by subtracting healthy brain tissue from both hemispheres. Brain edema was examined as a percent volume increase in the ischemic compared with the contralateral hemisphere. The incidence and area of hemorrhages were evaluated by diaminobenzidine staining (D5905; Sigma-Aldrich, Deisenhofen, Germany) in sections obtained +1.0, ±0.0, −1.0, and −2.0 mm rostral to bregma. Experiments were performed with government approval (LANUV, Recklinghausen, Germany) in accordance with EU Directive 2010/63/ EU. Groups were strictly randomized and experimenters

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Stroke and myocardial infarction induce neutrophil extracellular trap release disrupting lymphoid organ structure and immunoglobulin secretion

Cited by 7 publications

References 48 publications

Differential action modes of Neutrophil Extracellular Trap-targeted drugs define T cell responses in SARS-CoV-2 infection

Differential action modes of Neutrophil Extracellular Trap-targeted drugs define T cell responses in SARS-CoV-2 infection

Proteomic Characterization of 1000 Human and Murine Neutrophils Freshly Isolated From Blood and Sites of Sterile Inflammation

Delayed DNase-I Administration but Not Gasdermin-D Inhibition Induces Hemorrhagic Transformation After Transient Focal Cerebral Ischemia in Mice

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