The chymase mouse mast cell protease 4 degrades TNF, limits inflammation, and promotes survival in a model of sepsis.
Mouse mast cell protease 4 (mMCP-4), the mouse counterpart of human mast cell chymase, is thought to have proinflammatory effects in innate or adaptive immune responses associated with mast cell activation. However, human chymase can degrade the proinflammatory cytokine TNF, a mediator that can be produced by mast cells and many other cell types. We found that mMCP-4 can reduce levels of mouse mast cell-derived TNF in vitro through degradation of transmembrane and soluble TNF. We assessed the effects of interactions between mMCP-4 and TNF in vivo by analyzing the features of a classic model of polymicrobial sepsis, cecal ligation and puncture (CLP), in C57BL/6J-mMCP-4-deficient mice versus C57BL/6J wild-type mice, and in C57BL/6J-Kit(W-sh/W-sh) mice containing adoptively transferred mast cells that were either wild type or lacked mMCP-4, TNF, or both mediators. The mMCP-4-deficient mice exhibited increased levels of intraperitoneal TNF, higher numbers of peritoneal neutrophils, and increased acute kidney injury after CLP, and also had significantly higher mortality after this procedure. Our findings support the conclusion that mMCP-4 can enhance survival after CLP at least in part by limiting detrimental effects of TNF, and suggest that mast cell chymase may represent an important negative regulator of TNF in vivo.
Department of Pathology, Stanford University School of Medicine, California 94305-5324, USA. adrian.piliponsky@seattlechildrens.org
Adrian M
AM
Piliponsky
Ching-Cheng
CC
Chen
Eon J
EJ
Rios
Piper M
PM
Treuting
Asha
A
Lahiri
Magnus
M
Abrink
Gunnar
G
Pejler
Mindy
M
Tsai
Stephen J
SJ
Galli
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D053818:Chymases / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D007958:Leukocyte Count; D008026:Ligation; D008407:Mast Cells / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D018805:Sepsis / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D012697:Serine Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D012995:Solubility; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D012697:Serine Endopeptidases; C066932:mast cell protease 4; D053818:Chymases