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

• Published in: Nature medicine Vol. 13; no. 8; pp. 927 - 934
• Main Authors: Schulmistrat, Jan, Bulanova, Elena, Mirghomizadeh, Farhad, Orinska, Zane, Bulfone-Paus, Silvia, Budagian, Vadim, Giron-Michel, Julien, Nashkevich, Natalia, Schiemann, Florian, Brandt, Ernst, Maurer, Marcus, Metz, Martin, Paus, Ralf
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-08-2007
• Subjects: Animals; Bacteria; Biomedical research; Cellular biology; Chemokine CCL8; Chemotaxis; Chymases - metabolism; Cytokines; Down-Regulation; Escherichia coli - physiology; Gene Deletion; Infections; Interleukin-15 - deficiency; Interleukin-15 - genetics; Interleukin-15 - metabolism; Mast Cells - cytology; Mast Cells - metabolism; Mice; Mice, Knockout; Monocyte Chemoattractant Proteins - genetics; Rodents; Sepsis - genetics; Sepsis - metabolism; Sepsis - microbiology; Sepsis - pathology; Signal Transduction; Survival; Survival Rate; Transcription, Genetic - genetics; Up-Regulation
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm1615

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.