Bcr and Abr cooperate in negatively regulating acute inflammatory responses.
Bcr and Abr are GTPase-activating proteins for the small GTPase Rac. Both proteins are expressed in cells of the innate immune system, including neutrophils and macrophages. The function of Bcr has been linked to the negative regulation of neutrophil reactive oxygen species (ROS) production, but the function of Abr in the innate immune system was unknown. Here, we report that mice lacking both proteins are severely affected in two models of experimental endotoxemia, including exposure to Escherichia coli lipopolysaccharide and polymicrobial sepsis, with extensive microvascular leakage, resulting in severe pulmonary edema and hemorrhage. Additionally, in vivo-activated neutrophils of abr and bcr null mutant mice produced excessive tissue-damaging myeloperoxidase (MPO), elastase, and ROS. Moreover, the secretion of the tissue metalloproteinase MMP9 by monocytes and ROS by elicited macrophages was abnormally high. In comparison, ROS production from bone marrow monocytes was not significantly different from that of controls, and the exocytosis of neutrophil secondary and tertiary granule products, including lactoferrin, was normal. These data show that Abr and Bcr normally curb very specific functions of mature tissue innate immune cells, and that each protein has distinct as well as partly overlapping functions in the downregulation of inflammatory processes.
Cunnick
Jess M
JM
Division of Hematology/Oncology, Saban Research Institute of Childrens Hospital, Los Angeles, CA 90027, USA.
Schmidhuber
Sabine
S
Chen
Gang
G
Yu
Min
M
Yi
Sun-Ju
SJ
Cho
Young Jin
YJ
Kaartinen
Vesa
V
Minoo
Parviz
P
Warburton
David
D
Groffen
John
J
Heisterkamp
Nora
N
D000818:Animals; D003571:Cytochalasin B / Q000494:pharmacology; D019446:Endotoxemia / Q000382:microbiology; D004789:Enzyme Activation / Q000187:drug effects; D004926:Escherichia coli; D020690:GTPase-Activating Proteins; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D055370:Lung Injury / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010587:Phagocytosis / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D051562:Proto-Oncogene Proteins c-bcr / Q000172:deficiency / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
C484145:Abr protein, mouse; D020690:GTPase-Activating Proteins; D008070:Lipopolysaccharides; D011506:Proteins; D017382:Reactive Oxygen Species; D003571:Cytochalasin B; D009240:N-Formylmethionine Leucyl-Phenylalanine; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr; D020744:rac GTP-Binding Proteins
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