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| Content Provider | frontiers |
|---|---|
| Author | Hazeldine, Jon Dinsdale, Robert J. Harrison, Paul Lord, Janet M. |
| Abstract | Major traumatic injury induces significant remodelling of the circulating neutrophil pool and loss of bactericidal function. Although a well-described phenomenon, research to date has only analysed blood samples acquired post-hospital admission, and the mechanisms that initiate compromised neutrophil function post-injury are therefore poorly understood. Here, we analysed pre-hospital blood samples acquired from 62 adult trauma patients (mean age 44 years, range 19-95 years) within 1-hour of injury (mean time to sample 39 minutes, range 13-59 minutes). 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 hours). 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. |
| ISSN | 16643224 |
| DOI | 10.3389/fimmu.2019.00685 |
| Volume Number | 10 |
| Journal | Frontiers in Immunology |
| Language | English |
| Publisher Date | 2019-04-02 |
| Access Restriction | Open |
| Subject Keyword | Immune suppression Mitochondrial-derived damage associated molecular patterns Trauma Neutrophil (PMN) Neutrophil extracelluar traps |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Allergy Immunology |
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