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

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          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.

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          Most cited references56

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          Origin and physiological roles of inflammation.

          Ruslan Medzhitov (2008)
          Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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            CD56bright natural killer (NK) cells: an important NK cell subset.

            Aurelie Poli, Tatiana Michel, Maud Thérésine … (2009)
            Human natural killer (NK) cells can be subdivided into different populations based on the relative expression of the surface markers CD16 and CD56. The two major subsets are CD56(bright) CD16(dim/) (-) and CD56(dim) CD16(+), respectively. In this review, we will focus on the CD56(bright) NK cell subset. These cells are numerically in the minority in peripheral blood but constitute the majority of NK cells in secondary lymphoid tissues. They are abundant cytokine producers but are only weakly cytotoxic before activation. Recent data suggest that under certain conditions, they have immunoregulatory properties, and that they are probably immediate precursors of CD56(dim) NK cells. CD56(bright) NK cell percentages are expanded or reduced in a certain number of diseases, but the significance of these variations is not yet clear.
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              Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene.

              S Dennler, S Itoh, D Vivien … (1998)
              Smad proteins play a key role in the intracellular signalling of transforming growth factor beta (TGF beta), which elicits a large variety of cellular responses. Upon TGF beta receptor activation, Smad2 and Smad3 become phosphorylated and form heteromeric complexes with Smad4. These complexes translocate to the nucleus where they control expression of target genes. However, the mechanism by which Smads mediate transcriptional regulation is largely unknown. Human plasminogen activator inhibitor-1 (PAI-1) is a gene that is potently induced by TGF beta. Here we report the identification of Smad3/Smad4 binding sequences, termed CAGA boxes, within the promoter of the human PAI-1 gene. The CAGA boxes confer TGF beta and activin, but not bone morphogenetic protein (BMP) stimulation to a heterologous promoter reporter construct. Importantly, mutation of the three CAGA boxes present in the PAI-1 promoter was found to abolish TGF beta responsiveness. Thus, CAGA elements are essential and sufficient for the induction by TGF beta. In addition, TGFbeta induces the binding of a Smad3/Smad4-containing nuclear complex to CAGA boxes. Furthermore, bacterially expressed Smad3 and Smad4 proteins, but not Smad1 nor Smad2 protein, bind directly to this sequence in vitro. The presence of this box in TGF beta-responsive regions of several other genes suggests that this may be a widely used motif in TGF beta-regulated transcription.
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                Author and article information

                Contributors
                Stefanie B. Flohé
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 13 April 2019
                Publication date Collection: May 2019
                Publication date (Electronic): 13 April 2019
                Volume: 43
                Pages: 380-391
                Affiliations
                [a ]Department of Orthopedics and Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
                [b ]Siegfried Weller Institute for Trauma Research, University of Tübingen, Tübingen, Germany
                [c ]Leibniz Research Centre for Working Environment and Human Factors, IfADo, TU-Dortmund, Dortmund, Germany
                [d ]Institute of Clinical and Experimental Trauma-Immunology, University of Ulm, Ulm, Germany
                [e ]Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
                [f ]Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
                [g ]Department of Hand- and Trauma Surgery, University Hospital Dusseldorf, University Dusseldorf, Dusseldorf, Germany
                Author notes
                [* ]Corresponding author at: Department of Trauma Surgery, University Hospital Essen, Hufelandstr. 55, D-45147 Essen, Germany. stefanie.flohe@ 123456uk-essen.de
                Article
                Publisher ID: S2352-3964(19)30252-X
                DOI: 10.1016/j.ebiom.2019.04.018
                PMC ID: 6557805
                PubMed ID: 30992245
                SO-VID: 38f98754-88ff-417e-92e0-a7ec20dd4e05
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 14 January 2019
                Date revision received : 18 March 2019
                Date accepted : 8 April 2019
                Categories
                Subject: Research paper

                Keywords: natural killer cells,opportunistic infections,interferon gamma,interleukin 12,transforming growth factor receptor,immunosuppression
                Data availability:
                Keywords: natural killer cells, opportunistic infections, interferon gamma, interleukin 12, transforming growth factor receptor, immunosuppression

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