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Circulating growth/differentiation factor 15 is associated with human CD56bright natural killer cell dysfunction and nosocomial infection in severe systemic inflammation.

ABSTRACT: BACKGROUND:Systemic inflammation induced by sterile or infectious insults is associated with an enhanced susceptibility to life-threatening opportunistic, mostly bacterial, infections due to unknown pathogenesis. Natural killer (NK) cells contribute to the defence against bacterial infections through the release of Interferon (IFN) ? in response to Interleukin (IL) 12. Considering the relevance of NK cells in the immune defence we investigated whether the function of NK cells is disturbed in patients suffering from serious systemic inflammation. METHODS:NK cells from severely injured patients were analysed from the first day after the initial inflammatory insult until the day of discharge in terms of IL-12 receptor signalling and IFN-? synthesis. FINDINGS:During systemic inflammation, the expression of the IL-12 receptor ?2 chain, phosphorylation of signal transducer and activation 4, and IFN-? production on/in NK cells was impaired upon exposure to Staphylococcus aureus. The profound suppression of NK cells developed within 24?h after the initial insult and persisted for several weeks. NK cells displayed signs of exhaustion. Extrinsic changes were mediated by the early and long-lasting presence of growth/differentiation factor (GDF) 15 in the circulation that signalled through the transforming growth factor ? receptor I and activated Smad1/5. Moreover, the concentration of GDF-15 in the serum inversely correlated with the IL-12 receptor ?2 expression on NK cells and was enhanced in patients who later acquired septic complications. INTERPRETATION:GDF-15 is associated with the development of NK cell dysfunction during systemic inflammation and might represent a novel target to prevent nosocomial infections. FUND: The study was supported by the Department of Orthopaedics and Trauma Surgery, University Hospital Essen.

SUBMITTER: Kleinertz H

PROVIDER: S-EPMC6557805 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Circulating growth/differentiation factor 15 is associated with human CD56<sup>bright</sup> natural killer cell dysfunction and nosocomial infection in severe systemic inflammation.

Kleinertz Holger H Hepner-Schefczyk Monika M Ehnert Sabrina S Claus Maren M Halbgebauer Rebecca R Boller Lea L Huber-Lang Markus M Cinelli Paolo P Kirschning Carsten C Flohé Sascha S Sander André A Waydhas Christian C Vonderhagen Sonja S Jäger Marcus M Dudda Marcel M Watzl Carsten C Flohé Stefanie B SB

EBioMedicine 20190413

<h4>Background</h4>Systemic inflammation induced by sterile or infectious insults is associated with an enhanced susceptibility to life-threatening opportunistic, mostly bacterial, infections due to unknown pathogenesis. Natural killer (NK) cells contribute to the defence against bacterial infections through the release of Interferon (IFN) γ in response to Interleukin (IL) 12. Considering the relevance of NK cells in the immune defence we investigated whether the function of NK cells is disturbe ...[more]

PMID: 30992245

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Project description:BackgroundThe mechanisms driving systemic effects consequent pulmonary nanoparticle exposure remain unclear. Recent work has established the existence of an indirect process by which factors released from the lung into the circulation promote systemic inflammation and cellular dysfunction, particularly on the vasculature. However, the composition of circulating contributing factors and how they are produced remains unknown. Evidence suggests matrix protease involvement; thus, here we used a well-characterized multi-walled carbon nanotube (MWCNT) oropharyngeal aspiration model with known vascular effects to assess the distinct contribution of nanoparticle-induced peptide fragments in driving systemic pathobiology.ResultsData-independent mass spectrometry enabled the unbiased quantitative characterization of 841 significant MWCNT-responses within an enriched peptide fraction, with 567 of these factors demonstrating significant correlation across animal-paired bronchoalveolar lavage and serum biofluids. A database search curated for known matrix protease substrates and predicted signaling motifs enabled identification of 73 MWCNT-responsive peptides, which were significantly associated with an abnormal cardiovascular phenotype, extracellular matrix organization, immune-inflammatory processes, cell receptor signaling, and a MWCNT-altered serum exosome population. Production of a diverse peptidomic response was supported by a wide number of upregulated matrix and lysosomal proteases in the lung after MWCNT exposure. The peptide fraction was then found bioactive, producing endothelial cell inflammation and vascular dysfunction ex vivo akin to that induced with whole serum. Results implicate receptor ligand functionality in driving systemic effects, exemplified by an identified 59-mer thrombospondin fragment, replete with CD36 modulatory motifs, that when synthesized produced an anti-angiogenic response in vitro matching that of the peptide fraction. Other identified peptides point to integrin ligand functionality and more broadly to a diversity of receptor-mediated bioactivity induced by the peptidomic response to nanoparticle exposure.ConclusionThe present study demonstrates that pulmonary-sequestered nanoparticles, such as multi-walled carbon nanotubes, acutely upregulate a diverse profile of matrix proteases, and induce a complex peptidomic response across lung and blood compartments. The serum peptide fraction, having cell-surface receptor ligand properties, conveys peripheral bioactivity in promoting endothelial cell inflammation, vasodilatory dysfunction and inhibiting angiogenesis. Results here establish peptide fragments as indirect, non-cytokine mediators and putative biomarkers of systemic health outcomes from nanoparticle exposure.

Dataset Information

Circulating growth/differentiation factor 15 is associated with human CD56bright natural killer cell dysfunction and nosocomial infection in severe systemic inflammation.

Publications

Circulating growth/differentiation factor 15 is associated with human CD56<sup>bright</sup> natural killer cell dysfunction and nosocomial infection in severe systemic inflammation.

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