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 journalArticlepeer-review

88 Scopus citations

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 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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