“Rogue” neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury – studies in human, macaque and rat LPS-inflammation models
Background and objectiveThe correlation (Rs > 0.7) of neutrophils expressing the dual endothelin1/signal peptide receptor (DEspR+CD11b+/CD66b+) with severity of hypoxemia (SF-ratio) and multi-organ failure (SOFA-score) in patients with acute respiratory distress syndrome (ARDS) suggest the hy...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1008390/full |
| _version_ | 1811242910216093696 |
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| author | Saskia Carstensen Meike Müller Glaiza L. A. Tan Khristine Amber Pasion Jens M. Hohlfeld Jens M. Hohlfeld Jens M. Hohlfeld Victoria L. M. Herrera Nelson Ruiz-Opazo |
| author_facet | Saskia Carstensen Meike Müller Glaiza L. A. Tan Khristine Amber Pasion Jens M. Hohlfeld Jens M. Hohlfeld Jens M. Hohlfeld Victoria L. M. Herrera Nelson Ruiz-Opazo |
| author_sort | Saskia Carstensen |
| collection | DOAJ |
| description | Background and objectiveThe correlation (Rs > 0.7) of neutrophils expressing the dual endothelin1/signal peptide receptor (DEspR+CD11b+/CD66b+) with severity of hypoxemia (SF-ratio) and multi-organ failure (SOFA-score) in patients with acute respiratory distress syndrome (ARDS) suggest the hypothesis that the DEspR+ neutrophil-subset is an actionable therapeutic target in ARDS. To test this hypothesis, we conducted in vivo studies to validate DEspR+ neutrophil-subset as therapeutic target and test efficacy of DEspR-inhibition in acute neutrophilic hyperinflammation models.MethodsWe performed tests in lipopolysaccharide (LPS)-induced acute neutrophilic inflammation in three species – human, rhesus macaque, rat – with increasing dose-dependent severity. We measured DEspR+CD66b+ neutrophils in bronchoalveolar lavage fluid (BALF) in healthy volunteers (HVs) 24-hours after segmental LPS-challenge by ChipCytometry, and DEspR+CD11b+ neutrophils in whole blood and BALF in an LPS-induced transient acute lung injury (ALI) model in macaques. We determined anti-DEspR antibody efficacy in vivo in LPS-ALI macaque model and in high-mortality LPS-induced encephalopathy in hypertensive rats.ResultsChipCytometry detected increased BALF total neutrophil and DEspR+CD66b+ neutrophil counts after segmental LPS-challenge compared to baseline (P =0.034), as well as increased peripheral neutrophil counts and neutrophil-lymphocyte ratio (NLR) compared to pre-LPS level (P <0.05). In the LPS-ALI macaque model, flow cytometry detected increased DEspR+ and DEspR[-] neutrophils in BALF, which was associated with moderate-severe hypoxemia. After determining pharmacokinetics of single-dose anti-DEspR[hu6g8] antibody, one-time pre-LPS anti-DEspR treatment reduced hypoxemia (P =0.03) and neutrophil influx into BALF (P =0.0001) in LPS-ALI vs vehicle mock-treated LPS-ALI macaques. Ex vivo live cell imaging of macaque neutrophils detected greater “intrinsic adhesion to hard-surface” in DEspR+ vs DEspR[-] neutrophils (P <0.001). Anti-DEspR[hu6g8] antibody abrogated intrinsic high adhesion in DEspR+ neutrophils, but not in DEspR[-] neutrophils (P <0.001). In the LPS-encephalopathy rat model, anti-DEspR[10a3] antibody treatment increased median survival (P =0.0007) and exhibited brain target engagement and bioeffects.ConclusionDetection of increased DEspR+ neutrophil-subset in human BALF after segmental LPS-challenge supports the correlation of circulating DEspR+ neutrophil counts with severity measure (SOFA-score) in ARDS. Efficacy and safety of targeted inhibition of DEspR+CD11b+ neutrophil-subset in LPS-induced transient-ALI and high-mortality encephalopathy models identify a potential therapeutic target for neutrophil-mediated secondary tissue injury. |
| first_indexed | 2024-04-12T13:58:53Z |
| format | Article |
| id | doaj.art-a402768b25f34218b6105a4db2b4c356 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T13:58:53Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a402768b25f34218b6105a4db2b4c3562022-12-22T03:30:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-10-011310.3389/fimmu.2022.10083901008390“Rogue” neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury – studies in human, macaque and rat LPS-inflammation modelsSaskia Carstensen0Meike Müller1Glaiza L. A. Tan2Khristine Amber Pasion3Jens M. Hohlfeld4Jens M. Hohlfeld5Jens M. Hohlfeld6Victoria L. M. Herrera7Nelson Ruiz-Opazo8Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Department of Biomarker Analysis and Development, Hannover, GermanyFraunhofer Institute for Toxicology and Experimental Medicine ITEM, Department of Biomarker Analysis and Development, Hannover, GermanyWhitaker Cardiovascular Institute and Department of Medicine, Boston University School of Medicine, Boston MA, United StatesWhitaker Cardiovascular Institute and Department of Medicine, Boston University School of Medicine, Boston MA, United StatesFraunhofer Institute for Toxicology and Experimental Medicine ITEM, Department of Biomarker Analysis and Development, Hannover, GermanyDepartment of Respiratory Medicine, Hannover Medical School, Hannover, GermanyMember of the German Center for Lung Research (DZL), Hannover, GermanyWhitaker Cardiovascular Institute and Department of Medicine, Boston University School of Medicine, Boston MA, United StatesWhitaker Cardiovascular Institute and Department of Medicine, Boston University School of Medicine, Boston MA, United StatesBackground and objectiveThe correlation (Rs > 0.7) of neutrophils expressing the dual endothelin1/signal peptide receptor (DEspR+CD11b+/CD66b+) with severity of hypoxemia (SF-ratio) and multi-organ failure (SOFA-score) in patients with acute respiratory distress syndrome (ARDS) suggest the hypothesis that the DEspR+ neutrophil-subset is an actionable therapeutic target in ARDS. To test this hypothesis, we conducted in vivo studies to validate DEspR+ neutrophil-subset as therapeutic target and test efficacy of DEspR-inhibition in acute neutrophilic hyperinflammation models.MethodsWe performed tests in lipopolysaccharide (LPS)-induced acute neutrophilic inflammation in three species – human, rhesus macaque, rat – with increasing dose-dependent severity. We measured DEspR+CD66b+ neutrophils in bronchoalveolar lavage fluid (BALF) in healthy volunteers (HVs) 24-hours after segmental LPS-challenge by ChipCytometry, and DEspR+CD11b+ neutrophils in whole blood and BALF in an LPS-induced transient acute lung injury (ALI) model in macaques. We determined anti-DEspR antibody efficacy in vivo in LPS-ALI macaque model and in high-mortality LPS-induced encephalopathy in hypertensive rats.ResultsChipCytometry detected increased BALF total neutrophil and DEspR+CD66b+ neutrophil counts after segmental LPS-challenge compared to baseline (P =0.034), as well as increased peripheral neutrophil counts and neutrophil-lymphocyte ratio (NLR) compared to pre-LPS level (P <0.05). In the LPS-ALI macaque model, flow cytometry detected increased DEspR+ and DEspR[-] neutrophils in BALF, which was associated with moderate-severe hypoxemia. After determining pharmacokinetics of single-dose anti-DEspR[hu6g8] antibody, one-time pre-LPS anti-DEspR treatment reduced hypoxemia (P =0.03) and neutrophil influx into BALF (P =0.0001) in LPS-ALI vs vehicle mock-treated LPS-ALI macaques. Ex vivo live cell imaging of macaque neutrophils detected greater “intrinsic adhesion to hard-surface” in DEspR+ vs DEspR[-] neutrophils (P <0.001). Anti-DEspR[hu6g8] antibody abrogated intrinsic high adhesion in DEspR+ neutrophils, but not in DEspR[-] neutrophils (P <0.001). In the LPS-encephalopathy rat model, anti-DEspR[10a3] antibody treatment increased median survival (P =0.0007) and exhibited brain target engagement and bioeffects.ConclusionDetection of increased DEspR+ neutrophil-subset in human BALF after segmental LPS-challenge supports the correlation of circulating DEspR+ neutrophil counts with severity measure (SOFA-score) in ARDS. Efficacy and safety of targeted inhibition of DEspR+CD11b+ neutrophil-subset in LPS-induced transient-ALI and high-mortality encephalopathy models identify a potential therapeutic target for neutrophil-mediated secondary tissue injury.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1008390/fullneutrophil subsetDEspRLPS-acute inflammation tissue injury modelsacute lung injuryLPS-brain encephalopathysegmental LPS challenge |
| spellingShingle | Saskia Carstensen Meike Müller Glaiza L. A. Tan Khristine Amber Pasion Jens M. Hohlfeld Jens M. Hohlfeld Jens M. Hohlfeld Victoria L. M. Herrera Nelson Ruiz-Opazo “Rogue” neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury – studies in human, macaque and rat LPS-inflammation models Frontiers in Immunology neutrophil subset DEspR LPS-acute inflammation tissue injury models acute lung injury LPS-brain encephalopathy segmental LPS challenge |
| title | “Rogue” neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury – studies in human, macaque and rat LPS-inflammation models |
| title_full | “Rogue” neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury – studies in human, macaque and rat LPS-inflammation models |
| title_fullStr | “Rogue” neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury – studies in human, macaque and rat LPS-inflammation models |
| title_full_unstemmed | “Rogue” neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury – studies in human, macaque and rat LPS-inflammation models |
| title_short | “Rogue” neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury – studies in human, macaque and rat LPS-inflammation models |
| title_sort | rogue neutrophil subset despr cd11b cd66b immunotype is an actionable therapeutic target for neutrophilic inflammation mediated tissue injury studies in human macaque and rat lps inflammation models |
| topic | neutrophil subset DEspR LPS-acute inflammation tissue injury models acute lung injury LPS-brain encephalopathy segmental LPS challenge |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1008390/full |
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