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Molecular and Cellular Biology, November 2009, p. 5742-5750, Vol. 29, No. 21
0270-7306/09/$08.00+0 doi:10.1128/MCB.00357-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Bcr and Abr Cooperate in Negatively Regulating Acute Inflammatory Responses
Jess M. Cunnick,1,
Sabine Schmidhuber,1
Gang Chen,1,
Min Yu,1
Sun-Ju Yi,1
Young Jin Cho,1,
Vesa Kaartinen,1,¶
Parviz Minoo,3
David Warburton,4,5
John Groffen,1,2,3 and
Nora Heisterkamp1,2,3*
Division of Hematology/Oncology, Saban Research Institute of Childrens Hospital, Los Angeles, California 90027,1 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033,2 Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033,3 Developmental Biology Program, Saban Research Institute of Childrens Hospital, Los Angeles, California 90027,4 Department of Surgery, Saban Research Institute of Childrens Hospital, Los Angeles, California 900275
Received 19 March 2009/ Returned for modification 12 May 2009/ Accepted 11 August 2009
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.
* Corresponding author. Mailing address: Division of Hematology/Oncology, Ms#54, Childrens Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027. Phone: (323) 361-4595. Fax: (323) 671-3613. E-mail: heisterk{at}hsc.usc.edu
Published ahead of print on 24 August 2009.
Present address: The Commonwealth Medical College, 501 Madison Ave., Scranton, PA 18510.
Present address: Entomology Department, University of California, Riverside, CA 92521.
¶ Present address: Department of Biologic and Material Sciences, University of Michigan, School of Dentistry, Ann Arbor, MI.
Molecular and Cellular Biology, November 2009, p. 5742-5750, Vol. 29, No. 21
0270-7306/09/$08.00+0 doi:10.1128/MCB.00357-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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