A targetable 'rogue' neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDS
© 2022. The Author(s)..
Neutrophil-mediated secondary tissue injury underlies acute respiratory distress syndrome (ARDS) and progression to multi-organ-failure (MOF) and death, processes linked to COVID-19-ARDS. This secondary tissue injury arises from dysregulated neutrophils and neutrophil extracellular traps (NETs) intended to kill pathogens, but instead cause cell-injury. Insufficiency of pleiotropic therapeutic approaches delineate the need for inhibitors of dysregulated neutrophil-subset(s) that induce subset-specific apoptosis critical for neutrophil function-shutdown. We hypothesized that neutrophils expressing the pro-survival dual endothelin-1/VEGF-signal peptide receptor, DEspR, are apoptosis-resistant like DEspR+ cancer-cells, hence comprise a consequential pathogenic neutrophil-subset in ARDS and COVID-19-ARDS. Here, we report the significant association of increased peripheral DEspR+CD11b+ neutrophil-counts with severity and mortality in ARDS and COVID-19-ARDS, and intravascular NET-formation, in contrast to DEspR[-] neutrophils. We detect DEspR+ neutrophils and monocytes in lung tissue patients in ARDS and COVID-19-ARDS, and increased neutrophil RNA-levels of DEspR ligands and modulators in COVID-19-ARDS scRNA-seq data-files. Unlike DEspR[-] neutrophils, DEspR+CD11b+ neutrophils exhibit delayed apoptosis, which is blocked by humanized anti-DEspR-IgG4S228P antibody, hu6g8, in ex vivo assays. Ex vivo live-cell imaging of Rhesus-derived DEspR+CD11b+ neutrophils showed hu6g8 target-engagement, internalization, and induction of apoptosis. Altogether, data identify DEspR+CD11b+ neutrophils as a targetable 'rogue' neutrophil-subset associated with severity and mortality in ARDS and COVID-19-ARDS.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Scientific reports - 12(2022), 1 vom: 04. Apr., Seite 5583 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Herrera, Victoria L M [VerfasserIn] |
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| Links: |
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| Themen: |
Journal Article |
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| Anmerkungen: |
Date Completed 06.04.2022 Date Revised 17.05.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41598-022-09343-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM339096918 |
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| 100 | 1 | |a Herrera, Victoria L M |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A targetable 'rogue' neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDS |
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| 500 | |a Date Revised 17.05.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a Neutrophil-mediated secondary tissue injury underlies acute respiratory distress syndrome (ARDS) and progression to multi-organ-failure (MOF) and death, processes linked to COVID-19-ARDS. This secondary tissue injury arises from dysregulated neutrophils and neutrophil extracellular traps (NETs) intended to kill pathogens, but instead cause cell-injury. Insufficiency of pleiotropic therapeutic approaches delineate the need for inhibitors of dysregulated neutrophil-subset(s) that induce subset-specific apoptosis critical for neutrophil function-shutdown. We hypothesized that neutrophils expressing the pro-survival dual endothelin-1/VEGF-signal peptide receptor, DEspR, are apoptosis-resistant like DEspR+ cancer-cells, hence comprise a consequential pathogenic neutrophil-subset in ARDS and COVID-19-ARDS. Here, we report the significant association of increased peripheral DEspR+CD11b+ neutrophil-counts with severity and mortality in ARDS and COVID-19-ARDS, and intravascular NET-formation, in contrast to DEspR[-] neutrophils. We detect DEspR+ neutrophils and monocytes in lung tissue patients in ARDS and COVID-19-ARDS, and increased neutrophil RNA-levels of DEspR ligands and modulators in COVID-19-ARDS scRNA-seq data-files. Unlike DEspR[-] neutrophils, DEspR+CD11b+ neutrophils exhibit delayed apoptosis, which is blocked by humanized anti-DEspR-IgG4S228P antibody, hu6g8, in ex vivo assays. Ex vivo live-cell imaging of Rhesus-derived DEspR+CD11b+ neutrophils showed hu6g8 target-engagement, internalization, and induction of apoptosis. Altogether, data identify DEspR+CD11b+ neutrophils as a targetable 'rogue' neutrophil-subset associated with severity and mortality in ARDS and COVID-19-ARDS | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 700 | 1 | |a Walkey, Allan J |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Mai Q |e verfasserin |4 aut | |
| 700 | 1 | |a Gromisch, Christopher M |e verfasserin |4 aut | |
| 700 | 1 | |a Mosaddhegi, Julie Z |e verfasserin |4 aut | |
| 700 | 1 | |a Gromisch, Matthew S |e verfasserin |4 aut | |
| 700 | 1 | |a Jundi, Bakr |e verfasserin |4 aut | |
| 700 | 1 | |a Lukassen, Soeren |e verfasserin |4 aut | |
| 700 | 1 | |a Carstensen, Saskia |e verfasserin |4 aut | |
| 700 | 1 | |a Denis, Ridiane |e verfasserin |4 aut | |
| 700 | 1 | |a Belkina, Anna C |e verfasserin |4 aut | |
| 700 | 1 | |a Baron, Rebecca M |e verfasserin |4 aut | |
| 700 | 1 | |a Pinilla-Vera, Mayra |e verfasserin |4 aut | |
| 700 | 1 | |a Mueller, Meike |e verfasserin |4 aut | |
| 700 | 1 | |a Kimberly, W Taylor |e verfasserin |4 aut | |
| 700 | 1 | |a Goldstein, Joshua N |e verfasserin |4 aut | |
| 700 | 1 | |a Lehmann, Irina |e verfasserin |4 aut | |
| 700 | 1 | |a Shih, Angela R |e verfasserin |4 aut | |
| 700 | 1 | |a Eils, Roland |e verfasserin |4 aut | |
| 700 | 1 | |a Levy, Bruce D |e verfasserin |4 aut | |
| 700 | 1 | |a Ruiz-Opazo, Nelson |e verfasserin |4 aut | |
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