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

Zane Orinska, Marcus Maurer, Farhad Mirghomizadeh, Elena Bulanova, Martin Metz, Natalia Nashkevich, Florian Schiemann, Jan Schulmistrat, Vadim Budagian, Julien Giron-Michel, Ernst Brandt, Ralf Paus, Silvia Bulfone-Paus

Research output: Contribution to journalArticle

81 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)927-934
Number of pages8
JournalNature Medicine
Volume13
Issue number8
DOIs
StatePublished - Aug 1 2007
Externally publishedYes

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Chymases
Interleukin-15
Mast Cells
Sepsis
Peptide Hydrolases
Neutrophil Activation
Chemokines
Lipopolysaccharides
Peritonitis
Gram-Negative Bacteria
Bacteria
Punctures
Chemical activation
Ligation
Cytokines
Processing

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Orinska, Z., Maurer, M., Mirghomizadeh, F., Bulanova, E., Metz, M., Nashkevich, N., ... Bulfone-Paus, S. (2007). IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities. Nature Medicine, 13(8), 927-934. https://doi.org/10.1038/nm1615

IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities. / Orinska, Zane; Maurer, Marcus; Mirghomizadeh, Farhad; Bulanova, Elena; Metz, Martin; Nashkevich, Natalia; Schiemann, Florian; Schulmistrat, Jan; Budagian, Vadim; Giron-Michel, Julien; Brandt, Ernst; Paus, Ralf; Bulfone-Paus, Silvia.

In: Nature Medicine, Vol. 13, No. 8, 01.08.2007, p. 927-934.

Research output: Contribution to journalArticle

Orinska, Z, Maurer, M, Mirghomizadeh, F, Bulanova, E, Metz, M, Nashkevich, N, Schiemann, F, Schulmistrat, J, Budagian, V, Giron-Michel, J, Brandt, E, Paus, R & Bulfone-Paus, S 2007, 'IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities', Nature Medicine, vol. 13, no. 8, pp. 927-934. https://doi.org/10.1038/nm1615
Orinska Z, Maurer M, Mirghomizadeh F, Bulanova E, Metz M, Nashkevich N et al. IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities. Nature Medicine. 2007 Aug 1;13(8):927-934. https://doi.org/10.1038/nm1615
Orinska, Zane ; Maurer, Marcus ; Mirghomizadeh, Farhad ; Bulanova, Elena ; Metz, Martin ; Nashkevich, Natalia ; Schiemann, Florian ; Schulmistrat, Jan ; Budagian, Vadim ; Giron-Michel, Julien ; Brandt, Ernst ; Paus, Ralf ; Bulfone-Paus, Silvia. / IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities. In: Nature Medicine. 2007 ; Vol. 13, No. 8. pp. 927-934.
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