title: Bcr and Abr cooperate in negatively regulating acute inflammatory responses.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Saban Research Institute of Childrens Hospital, Los Angeles, CA 90027, USA.
authors.forename: Jess M
authors.initials: JM
authors.lastname: Cunnick
authors.forename: Sabine
authors.initials: S
authors.lastname: Schmidhuber
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.forename: Sun-Ju
authors.initials: SJ
authors.lastname: Yi
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Cho
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.forename: John
authors.initials: J
authors.lastname: Groffen
authors.forename: Nora
authors.initials: N
authors.lastname: Heisterkamp
mesh_terms: 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
chemical_list: 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
references.citation: Blood. 2004 Aug 1;104(3):832-9
references.pmid: 15073033
references.citation: Immunity. 2000 Feb;12(2):201-10
references.pmid: 10714686
references.citation: J Clin Invest. 2006 Mar;116(3):695-702
references.pmid: 16485040
references.citation: J Biol Chem. 1993 Dec 25;268(36):27291-8
references.pmid: 8262969
references.citation: Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10282-6
references.pmid: 7479768
references.citation: Br J Surg. 2001 Jan;88(1):22-30
references.pmid: 11136305
references.citation: J Immunol. 2004 Nov 15;173(10):5971-9
references.pmid: 15528331
references.citation: J Immunol. 2003 Mar 15;170(6):3273-8
references.pmid: 12626586
references.citation: Pharmacol Ther. 2005 Sep;107(3):358-76
references.pmid: 15951020
references.citation: Dev Dyn. 2002 Apr;223(4):517-25
references.pmid: 11921339
references.citation: J Intern Med. 2005 Apr;257(4):319-28
references.pmid: 15788001
references.citation: J Cell Sci. 2004 Nov 1;117(Pt 23):5535-41
references.pmid: 15494376
references.citation: Development. 2001 Nov;128(21):4217-27
references.pmid: 11684658
references.citation: Nat Rev Mol Cell Biol. 2008 Sep;9(9):690-701
references.pmid: 18719708
references.citation: FEBS Lett. 2002 Sep 25;528(1-3):27-34
references.pmid: 12297274
references.citation: J Immunol Methods. 1996 Oct 16;197(1-2):139-50
references.pmid: 8890901
references.citation: Cell. 1995 Mar 10;80(5):719-28
references.pmid: 7889565
references.citation: Proc Soc Exp Biol Med. 1970 Apr;133(4):1384-7
references.pmid: 4245399
references.citation: Cell Immunol. 2005 Jun;235(2):92-7
references.pmid: 16157315
references.citation: Mol Cell Biol. 2007 Feb;27(3):899-911
references.pmid: 17116687
references.citation: J Cell Biol. 1996 May;133(4):895-910
references.pmid: 8666673
references.citation: Cell. 1994 Jan 28;76(2):301-14
references.pmid: 7507411
references.citation: Eur J Surg. 2002;168(4):204-14
references.pmid: 12440757
references.citation: Microbiol Immunol. 2004;48(11):807-15
references.pmid: 15557738
references.citation: Nature. 1985 Jun 27-Jul 3;315(6022):758-61
references.pmid: 2989703
references.citation: J Immunol. 1999 Jan 15;162(2):1120-6
references.pmid: 9916742
references.citation: Blood. 1997 May 15;89(10):3503-21
references.pmid: 9160655
references.citation: J Clin Invest. 2005 Sep;115(9):2444-53
references.pmid: 16127466
references.citation: Shock. 2005 Jan;23(1):11-7
references.pmid: 15614125
references.citation: Microbes Infect. 2003 Nov;5(14):1317-27
references.pmid: 14613775
references.citation: J Immunol. 1996 Jan 1;156(1):1-4
references.pmid: 8598448
references.citation: Inflamm Res. 1997 Oct;46(10):382-91
references.pmid: 9372309
references.citation: J Leukoc Biol. 2004 Apr;75(4):604-11
references.pmid: 14694182
references.citation: J Biol Chem. 1989 Oct 5;264(28):16378-82
references.pmid: 2674130
references.citation: Am J Physiol Cell Physiol. 2008 Nov;295(5):C1354-65
references.pmid: 18799653
references.citation: Immunopharmacology. 1994 Jul-Aug;28(1):1-18
references.pmid: 7928299
references.citation: J Immunol Methods. 2006 Apr 20;311(1-2):96-105
references.pmid: 16563426
references.citation: J Biol Chem. 1993 Aug 15;268(23):16903-6
references.pmid: 8349582
references.citation: Methods Mol Biol. 1997;75:301-4
references.pmid: 9276279
references.citation: Nature. 1991 May 30;351(6325):400-2
references.pmid: 1903516
references.citation: J Biol Chem. 2008 Feb 8;283(6):3023-3030
references.pmid: 18070886