Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G.
While the critical role of reactive oxygen intermediates (ROI) in the microbicidal activity of polymorphonuclear granulocytes is well established, the function of the nonoxidative effector mechanisms in vivo remains unclear. Here we show that mice deficient in the neutrophil granule serine proteases elastase and/or cathepsin G are susceptible to fungal infections, despite normal neutrophil development and recruitment. The protease deficiencies but not the absence of ROI leads to enhanced resistance to the lethal effects of endotoxin LPS, although normal levels of TNFalpha are produced. The data demonstrate a critical role of the nonoxidative effector mechanisms of neutrophils in host immunity and immunopathology and identify elastase and cathepsin G as effectors in the endotoxic shock cascade downstream of TNFalpha.
Tkalcevic
J
J
Department of Medicine, University College London, The Windeyer Institute of Medical Sciences, United Kingdom.
Novelli
M
M
Phylactides
M
M
Iredale
J P
JP
Segal
A W
AW
Roes
J
J
D000818:Animals; D001228:Aspergillosis / Q000276:immunology; D001232:Aspergillus fumigatus / Q000276:immunology; D056649:Cathepsin G; D002403:Cathepsins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D006098:Granulocytes / Q000166:cytology; D019272:Leukocyte Elastase / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000276:immunology*; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D012697:Serine Endopeptidases; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D002403:Cathepsins; D012697:Serine Endopeptidases; D056649:Cathepsin G; C534096:Ctsg protein, mouse; D019272:Leukocyte Elastase