Traumatic Injury and Exposure to Mitochondrial-Derived Damage Associated Molecular Patterns Suppresses Neutrophil Extracellular Trap Formation
Major traumatic injury induces significant remodeling of the circulating neutrophil pool and loss of bactericidal function. Although a well-described phenomenon, research to date has only analyzed blood samples acquired post-hospital admission, and the mechanisms that initiate compromised neutrophil...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00685/full |
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| author | Jon Hazeldine Jon Hazeldine Robert J. Dinsdale Robert J. Dinsdale Paul Harrison Paul Harrison Janet M. Lord Janet M. Lord Janet M. Lord |
| author_facet | Jon Hazeldine Jon Hazeldine Robert J. Dinsdale Robert J. Dinsdale Paul Harrison Paul Harrison Janet M. Lord Janet M. Lord Janet M. Lord |
| author_sort | Jon Hazeldine |
| collection | DOAJ |
| description | Major traumatic injury induces significant remodeling of the circulating neutrophil pool and loss of bactericidal function. Although a well-described phenomenon, research to date has only analyzed blood samples acquired post-hospital admission, and the mechanisms that initiate compromised neutrophil function post-injury are therefore poorly understood. Here, we analyzed pre-hospital blood samples acquired from 62 adult trauma patients (mean age 44 years, range 19–95 years) within 1 h of injury (mean time to sample 39 min, range 13–59 min). We found an immediate impairment in neutrophil extracellular trap (NET) generation in response to phorbol 12-myristate 13-acetate (PMA) stimulation, which persisted into the acute post-injury phase (4–72 h). Reduced NET generation was accompanied by reduced reactive oxygen species production, impaired activation of mitogen-activated protein kinases, and a reduction in neutrophil glucose uptake and metabolism to lactate. Pre-treating neutrophils from healthy subjects with mitochondrial-derived damage-associated molecular patterns (mtDAMPs), whose circulating levels were significantly increased in our trauma patients, reduced NET generation. This mtDAMP-induced impairment in NET formation was associated with an N-formyl peptide mediated activation of AMP-activated protein kinase (AMPK), a negative regulator of aerobic glycolysis and NET formation. Indeed, activation of AMPK via treatment with the AMP-mimetic AICAR significantly reduced neutrophil lactate production in response to PMA stimulation, a phenomenon that we also observed for neutrophils pre-treated with mtDAMPs. Furthermore, the impairment in NET generation induced by mtDAMPs was partially ameliorated by pre-treating neutrophils with the AMPK inhibitor compound C. Taken together, our data demonstrate an immediate trauma-induced impairment in neutrophil anti-microbial function and identify mtDAMP release as a potential initiator of acute post-injury neutrophil dysfunction. |
| first_indexed | 2024-12-19T07:41:22Z |
| format | Article |
| id | doaj.art-41032cf9fcdc4f90b9c762a6fb8045de |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T07:41:22Z |
| publishDate | 2019-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-41032cf9fcdc4f90b9c762a6fb8045de2022-12-21T20:30:26ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-04-011010.3389/fimmu.2019.00685441099Traumatic Injury and Exposure to Mitochondrial-Derived Damage Associated Molecular Patterns Suppresses Neutrophil Extracellular Trap FormationJon Hazeldine0Jon Hazeldine1Robert J. Dinsdale2Robert J. Dinsdale3Paul Harrison4Paul Harrison5Janet M. Lord6Janet M. Lord7Janet M. Lord8Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United KingdomNational Institute for Health Research Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomInstitute of Inflammation and Ageing, University of Birmingham, Birmingham, United KingdomScar Free Foundation Birmingham Centre for Burns Research, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomInstitute of Inflammation and Ageing, University of Birmingham, Birmingham, United KingdomScar Free Foundation Birmingham Centre for Burns Research, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomInstitute of Inflammation and Ageing, University of Birmingham, Birmingham, United KingdomNational Institute for Health Research Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomScar Free Foundation Birmingham Centre for Burns Research, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomMajor traumatic injury induces significant remodeling of the circulating neutrophil pool and loss of bactericidal function. Although a well-described phenomenon, research to date has only analyzed blood samples acquired post-hospital admission, and the mechanisms that initiate compromised neutrophil function post-injury are therefore poorly understood. Here, we analyzed pre-hospital blood samples acquired from 62 adult trauma patients (mean age 44 years, range 19–95 years) within 1 h of injury (mean time to sample 39 min, range 13–59 min). We found an immediate impairment in neutrophil extracellular trap (NET) generation in response to phorbol 12-myristate 13-acetate (PMA) stimulation, which persisted into the acute post-injury phase (4–72 h). Reduced NET generation was accompanied by reduced reactive oxygen species production, impaired activation of mitogen-activated protein kinases, and a reduction in neutrophil glucose uptake and metabolism to lactate. Pre-treating neutrophils from healthy subjects with mitochondrial-derived damage-associated molecular patterns (mtDAMPs), whose circulating levels were significantly increased in our trauma patients, reduced NET generation. This mtDAMP-induced impairment in NET formation was associated with an N-formyl peptide mediated activation of AMP-activated protein kinase (AMPK), a negative regulator of aerobic glycolysis and NET formation. Indeed, activation of AMPK via treatment with the AMP-mimetic AICAR significantly reduced neutrophil lactate production in response to PMA stimulation, a phenomenon that we also observed for neutrophils pre-treated with mtDAMPs. Furthermore, the impairment in NET generation induced by mtDAMPs was partially ameliorated by pre-treating neutrophils with the AMPK inhibitor compound C. Taken together, our data demonstrate an immediate trauma-induced impairment in neutrophil anti-microbial function and identify mtDAMP release as a potential initiator of acute post-injury neutrophil dysfunction.https://www.frontiersin.org/article/10.3389/fimmu.2019.00685/fullneutrophilsneutrophil extracellular trapstraumamitochondrial-derived DAMPsimmune suppression |
| spellingShingle | Jon Hazeldine Jon Hazeldine Robert J. Dinsdale Robert J. Dinsdale Paul Harrison Paul Harrison Janet M. Lord Janet M. Lord Janet M. Lord Traumatic Injury and Exposure to Mitochondrial-Derived Damage Associated Molecular Patterns Suppresses Neutrophil Extracellular Trap Formation Frontiers in Immunology neutrophils neutrophil extracellular traps trauma mitochondrial-derived DAMPs immune suppression |
| title | Traumatic Injury and Exposure to Mitochondrial-Derived Damage Associated Molecular Patterns Suppresses Neutrophil Extracellular Trap Formation |
| title_full | Traumatic Injury and Exposure to Mitochondrial-Derived Damage Associated Molecular Patterns Suppresses Neutrophil Extracellular Trap Formation |
| title_fullStr | Traumatic Injury and Exposure to Mitochondrial-Derived Damage Associated Molecular Patterns Suppresses Neutrophil Extracellular Trap Formation |
| title_full_unstemmed | Traumatic Injury and Exposure to Mitochondrial-Derived Damage Associated Molecular Patterns Suppresses Neutrophil Extracellular Trap Formation |
| title_short | Traumatic Injury and Exposure to Mitochondrial-Derived Damage Associated Molecular Patterns Suppresses Neutrophil Extracellular Trap Formation |
| title_sort | traumatic injury and exposure to mitochondrial derived damage associated molecular patterns suppresses neutrophil extracellular trap formation |
| topic | neutrophils neutrophil extracellular traps trauma mitochondrial-derived DAMPs immune suppression |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.00685/full |
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