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Soluble polysialylated NCAM: a novel player of the innate immune system in the lung

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Abstract

Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing “neutrophil extracellular traps”, which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes.

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Acknowledgments

We thank Christina Galuska and Kai Maass for many helpful discussions during preparation of the manuscript and proofreading as well as Werner Mink and Siegfried Kühnhardt for expert technical assistance. This work was supported by the Excellence Cluster Cardiopulmonary System (ECCPS) from the Deutsche Forschungsgemeinschaft (DFG) (Bonn, Germany), by the von Behring Röntgen Stiftung, by the BMBF-Clinical Research Group “Pneumonia” (Ministry for Education and Research, Berlin, Germany) as well as the LOEWE-program “Insect Biotechnology” (state of Hessen, Wiesbaden, Germany). RGS received financial support by the DFG in the framework of DFG Research Unit 548.

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Authors and Affiliations

  1. Institute of Biochemistry, Justus-Liebig-University, Giessen, Germany

    Christina Ulm, Mona Saffarzadeh, Sandra Müller, Gerlinde Prem, Peter Simon, Hildegard Geyer, Nils Bayer, Klaus T. Preissner, Rudolf Geyer & Sebastian P. Galuska

  2. Department of Internal Medicine II, Justus-Liebig-University, Giessen, Germany

    Poornima Mahavadi, Ingrid Henneke & Andreas Günther

  3. Institute of Anatomy and Cell Biology, Faculty of Medicine, Justus-Liebig-University, Giessen, Germany

    Farhan Saboor & Ralf Middendorff

  4. Institute of Physiology and Pathophysiology, Philipps-University, Marburg, Germany

    Susanne Rinné

  5. Institute of Veterinary Physiology and Biochemistry, Justus-Liebig-University, Giessen, Germany

    Thomas Lütteke

  6. Institute of Virology, Philipps-University, Marburg, Germany

    Eva Böttcher-Friebertshäuser

  7. Institute of Cellular Chemistry, Medical School, Hannover, Germany

    Rita Gerardy-Schahn, David Schwarzer & Martina Mühlenhoff

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  1. Christina Ulm
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Correspondence to Sebastian P. Galuska.

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M. Saffarzadeh, P. Mahavadi, and S. Müller contributed equally to this work.

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Ulm, C., Saffarzadeh, M., Mahavadi, P. et al. Soluble polysialylated NCAM: a novel player of the innate immune system in the lung. Cell. Mol. Life Sci. 70, 3695–3708 (2013). https://doi.org/10.1007/s00018-013-1342-0

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