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IL-15 constrains mast cell–dependent antibacterial defenses by suppressing chymase activities

Nature Medicine volume 13, pages 927–934 (2007)Cite this article

Abstract

Sepsis remains a global clinical problem. By using the mouse cecal ligation and puncture model of sepsis, here we identify an important aspect of mast cell (MC)-dependent, innate immune defenses against Gram-negative bacteria by demonstrating that MC protease activity is regulated by interleukin-15 (IL-15). Mouse MCs express both constitutive and lipopolysaccharide-inducible IL-15 and store it intracellularly. Deletion of Il15 in mice markedly increases chymase activities, leading to greater MC bactericidal responses, increased processing and activation of neutrophil-recruiting chemokines, and significantly higher survival rates of mice after septic peritonitis. By showing that intracellular IL-15 acts as a specific negative transcriptional regulator of a mouse MC chymase (mast cell protease-2), we provide evidence that defined MC protease activity is transcriptionally regulated by an intracellularly retained cytokine. Our results identify an unexpected breach in MC-dependent innate immune defenses against sepsis and suggest that inhibiting intracellular IL-15 in MCs may improve survival from sepsis.

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Figure 1: IL-15 downregulates survival after CLP.
Figure 2: Mouse MCs express IL-15.
Figure 3: MC protease activity is regulated by intracellular IL-15.
Figure 4: IL-15 modulates MC chymase activity.
Figure 5: Role of IL-15 in the regulation of chymase-mediated antimicrobial activity.

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Acknowledgements

We thank K. Streeck, D. Benner, S. Dinges and A. Bolch for technical support; C. Hölscher for IL-27 measurement; J. Urcioli for proofreading the manuscript; and J. Fingerle for advice. E. coli strain 2131 was a gift from O. Sperling and T.K. Lindhorst, Institute for Organic Chemistry, University of Kiel. This work was funded, in part, by grants from the Deutsche Forschungsgemeinschaft (DFG) to S.B.P. (SFB/TR22, A14), E.B. (SFB/TR22, A11), and M. Maurer (MA 1909/4-1/2). This work benefited from the European Union Network of Excellence Global Allergy and Asthma European Network (GA2LEN).

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Author notes

  1. Zane Orinska, Marcus Maurer and Farhad Mirghomizadeh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology and Cell Biology, Research Center Borstel, Parkallee 22, Borstel, 23845, Germany

    Zane Orinska, Farhad Mirghomizadeh, Elena Bulanova, Natalia Nashkevich, Florian Schiemann, Jan Schulmistrat, Vadim Budagian, Ernst Brandt & Silvia Bulfone-Paus

  2. Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité–Universitätsmedizin Berlin, Charitéplatz 1, Berlin, 10117, Germany

    Marcus Maurer & Martin Metz

  3. Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, 94305, California, USA

    Martin Metz

  4. U542 Institut National de la Santé et de la Recherche Médical (INSERM), Hôpital Paul Brousse, Villejuif, 94807, France

    Julien Giron-Michel

  5. Department of Dermatology, University Hospital Schleswig-Holstein, University of Lübeck, Ratzeburger Allee 160, Lübeck, 23538, Germany

    Ralf Paus

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Contributions

Z.O. conducted the in vitro studies. M. Maurer and M. Metz conducted the in vivo experiments. F.M. conducted MCP-related experiments (expression, promoter regulation). N.N. and J.S. conducted the microbicidal assays. F.S. and E. Brandt performed and evaluated CTAP-III processing experiments. V.B. contributed to RT-PCR analysis. J. G.-M. and E. Bulanova conducted confocal staining experiments. Z.O., M. Maurer, R.P. and S.B.-P. wrote the manuscript. Z.O. and S.B.-P. supervised the project.

Corresponding author

Correspondence to Silvia Bulfone-Paus.

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Orinska, Z., Maurer, M., Mirghomizadeh, F. et al. IL-15 constrains mast cell–dependent antibacterial defenses by suppressing chymase activities. Nat Med 13, 927–934 (2007). https://doi.org/10.1038/nm1615

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