A targetable ‘rogue’ neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDS
Abstract 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 (N...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-09343-1 |
| _version_ | 1819045520041050112 |
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| author | Victoria L. M. Herrera Allan J. Walkey Mai Q. Nguyen Christopher M. Gromisch Julie Z. Mosaddhegi Matthew S. Gromisch Bakr Jundi Soeren Lukassen Saskia Carstensen Ridiane Denis Anna C. Belkina Rebecca M. Baron Mayra Pinilla-Vera Meike Mueller W. Taylor Kimberly Joshua N. Goldstein Irina Lehmann Angela R. Shih Roland Eils Bruce D. Levy Nelson Ruiz-Opazo |
| author_facet | Victoria L. M. Herrera Allan J. Walkey Mai Q. Nguyen Christopher M. Gromisch Julie Z. Mosaddhegi Matthew S. Gromisch Bakr Jundi Soeren Lukassen Saskia Carstensen Ridiane Denis Anna C. Belkina Rebecca M. Baron Mayra Pinilla-Vera Meike Mueller W. Taylor Kimberly Joshua N. Goldstein Irina Lehmann Angela R. Shih Roland Eils Bruce D. Levy Nelson Ruiz-Opazo |
| author_sort | Victoria L. M. Herrera |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-21T10:29:52Z |
| format | Article |
| id | doaj.art-e3433c566fb14028b1c283831cb361bc |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-21T10:29:52Z |
| publishDate | 2022-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-e3433c566fb14028b1c283831cb361bc2022-12-21T19:07:14ZengNature PortfolioScientific Reports2045-23222022-04-0112112410.1038/s41598-022-09343-1A targetable ‘rogue’ neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDSVictoria L. M. Herrera0Allan J. Walkey1Mai Q. Nguyen2Christopher M. Gromisch3Julie Z. Mosaddhegi4Matthew S. Gromisch5Bakr Jundi6Soeren Lukassen7Saskia Carstensen8Ridiane Denis9Anna C. Belkina10Rebecca M. Baron11Mayra Pinilla-Vera12Meike Mueller13W. Taylor Kimberly14Joshua N. Goldstein15Irina Lehmann16Angela R. Shih17Roland Eils18Bruce D. Levy19Nelson Ruiz-Opazo20Whitaker Cardiovascular Institute and Department of Medicine, Boston University School of MedicineSection of Pulmonary and Critical Care, Department of Medicine, Boston University School of Medicine, and Boston Medical CenterWhitaker Cardiovascular Institute and Department of Medicine, Boston University School of MedicineWhitaker Cardiovascular Institute and Department of Medicine, Boston University School of MedicineWhitaker Cardiovascular Institute and Department of Medicine, Boston University School of MedicineWhitaker Cardiovascular Institute and Department of Medicine, Boston University School of MedicinePulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical SchoolCenter for Digital Health, Berlin Institute of Health and Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu BerlinFraunhofer Institute for Toxicology and Experimental MedicineGeneral Clinical Research Center, Boston University School of MedicineDepartment of Pathology and Laboratory Medicine, Flow Cytometry Core Facility, Boston University School of MedicinePulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical SchoolPulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical SchoolFraunhofer Institute for Toxicology and Experimental MedicineDivision of Neurocritical Care, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Emergency Medicine, Massachusetts General Hospital, Harvard Medical SchoolMolecular Epidemiology Unit, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health (BIH)Department of Pathology, Massachusetts General Hospital, Harvard Medical SchoolCenter for Digital Health, Berlin Institute of Health and Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu BerlinPulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical SchoolWhitaker Cardiovascular Institute and Department of Medicine, Boston University School of MedicineAbstract 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.https://doi.org/10.1038/s41598-022-09343-1 |
| spellingShingle | Victoria L. M. Herrera Allan J. Walkey Mai Q. Nguyen Christopher M. Gromisch Julie Z. Mosaddhegi Matthew S. Gromisch Bakr Jundi Soeren Lukassen Saskia Carstensen Ridiane Denis Anna C. Belkina Rebecca M. Baron Mayra Pinilla-Vera Meike Mueller W. Taylor Kimberly Joshua N. Goldstein Irina Lehmann Angela R. Shih Roland Eils Bruce D. Levy Nelson Ruiz-Opazo A targetable ‘rogue’ neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDS Scientific Reports |
| title | A targetable ‘rogue’ neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDS |
| title_full | A targetable ‘rogue’ neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDS |
| title_fullStr | A targetable ‘rogue’ neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDS |
| title_full_unstemmed | A targetable ‘rogue’ neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDS |
| title_short | A targetable ‘rogue’ neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDS |
| title_sort | targetable rogue neutrophil subset cd11b despr immunotype is associated with severity and mortality in acute respiratory distress syndrome ards and covid 19 ards |
| url | https://doi.org/10.1038/s41598-022-09343-1 |
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