Author: ["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"]
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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.Cite this article
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 