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) 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 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-γ synthesis. Findings During systemic inflammation, the expression of the IL-12 receptor β2 chain, phosphorylation of signal transducer and activation 4, and IFN-γ 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 β receptor I and activated Smad1/5. Moreover, the concentration of GDF-15 in the serum inversely correlated with the IL-12 receptor β2 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.

An Inverse Relationship Between c-Kit/CD117 and mTOR Confers NK Cell Dysregulation Late After Severe Injury

“…Three color staining of cell surface molecules was performed as described previously ( 19 ) using antibodies against CD3 (clone MEM-57, FITC-labeled, ImmunoTools, Friesoythe, Germany) and CD56 (clone CMSSB, APC-labeled, Thermo Fisher Scientific, Waltham, MA) in combination with one of the following PE-labeled antibodies: anti-IL-12Rβ2 (clone REA333, Miltenyi Biotec), anti-CD94 (clone DX22, BioLegend, San Diego, CA), anti-CD122 (clone TU27, BioLegend), anti-CD132 (clone TUGh4, BioLegend). Where indicated PE-Cy7-labeled antibodies against CD117 (clone 104D2, BioLegend) was used as a fourth color.…”

“…Intracellular staining of IFN-γ was performed as described previously ( 19 ) using antibodies against IFN-γ (clone 4S.B3, PE-labeled, BioLegend) in combination with anti-CD3 and anti-CD56. Intracellular staining of mTOR, EOMES, and T-bet was performed using the “FoxP3/Transcription Factor Staining Buffer Set” (Thermo Fisher Scientific) according to the manufacturer's instructions.…”

“…A recent study followed total NK cells for 5 d after trauma and observed a transient decrease in the expression of T-bet and IFN-γ ( 18 ). We have previously shown that CD56 bright NK cells are rapidly and long-lasting suppressed after major trauma in terms of IFN-γ synthesis in response to Staphylococcus aureus , a frequent cause of opportunistic infections after injury ( 19 ). We identified an impaired IL-12Rβ2 expression that was associated with decreased STAT4 activation and IFN-γ synthesis.…”

“…Although NK cells were similarly suppressed in IFN-γ synthesis from 24 h to at least 4 weeks after injury there were qualitative differences in the underlying mechanisms: extrinsic suppression of NK cells occurs early after injury and is mediated by a soluble factor that signals through the transforming growth factor (TGF) β receptor (TGF-βR) I. In addition, so far unknown endogenous changes establish in NK cells between 6 and 8 day after trauma that impair the IL-12/IFN-γ axis independent of the suppressive factor in the serum ( 19 ). Thus, the endogenous changes in NK cells overlap with the reported time window of cumulating infectious complications after trauma.…”

The impact of growth differentiation factor 15 on the risk of cardiovascular disease: evidence from Mendelian randomization study

“…Furthermore, Growth differentiation factor 15(GDF-15), the potential downstream of metformin, may play a crucial role in the process [3]. GDF-15 is a stress-responsive protein, involving in oxidative stress, in ammation and tissue hypoxia [4] [5], which could be an effective predictor and promising therapeutic targets for CVD. In PARADIGM-HF trial, Bouabdallaoui N, et al manifested that GDF-15 independently provided prognostic information in patients with heart failure with reduced ejection fraction(HFrEF) in which higher baseline and incremental GDF-15 levels were obviously relevant to mortality and all cardiovascular events, even after adjusting NT-proBNP and high-sensitivity cTnT [6].…”