IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities.
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.
Orinska
Zane
Z
Department of Immunology and Cell Biology, Research Center Borstel, Parkallee 22, 23845 Borstel, Germany.
Maurer
Marcus
M
Mirghomizadeh
Farhad
F
Bulanova
Elena
E
Metz
Martin
M
Nashkevich
Natalia
N
Schiemann
Florian
F
Schulmistrat
Jan
J
Budagian
Vadim
V
Giron-Michel
Julien
J
Brandt
Ernst
E
Paus
Ralf
R
Bulfone-Paus
Silvia
S
D000818:Animals; D054412:Chemokine CCL8; D002633:Chemotaxis; D053818:Chymases / Q000378:metabolism*; D015536:Down-Regulation; D004926:Escherichia coli / Q000502:physiology; D017353:Gene Deletion; D019409:Interleukin-15 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics; D018805:Sepsis / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D015398:Signal Transduction; D015996:Survival Rate; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation
C515454:Ccl8 protein, mouse; D054412:Chemokine CCL8; D019409:Interleukin-15; D018945:Monocyte Chemoattractant Proteins; D053818:Chymases