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.

The RacGAP ArhGAP15 is a master negative regulator of neutrophil functions

“…In line with this hypothesis, in a model of polymicrobial peritoneal sepsis, induced by severe cecal ligation and perforation, the absence of ArhGAP15 increased neutrophil migration to the site of infection, decreased bacterial growth and decompartmentalization, lowered systemic inflammation, and ultimately improved survival at one week. Although this is in apparent contrast to the increased mortality observed in Abr/Bcr double knockout mice at 48 hours after mild sepsis, 14 several reasons could account for this discrepancy. First, the functions of ArhGAP15 and Abr/Bcr probably do not completely overlap because of structural differences, such as the additional presence, in both Abr and Bcr, of a DH motif and a PDZ-binding domain.…”

“…In particular, these proteins negatively control most of the Rac-dependent functions in macrophages, 13 whereas, conversely, they only regulate specific activities in neutrophils. 14,15 Nonetheless, although the presence of other RacGAPs in neutrophils has been reported, 16,17 their activity has not been thoroughly investigated.…”

Dynamic Control of Excitatory Synapse Development by a Rac1 GEF/GAP Regulatory Complex

“…Bcr −/− mice display abnormal stress responses, increased aggression, and impairments in LTP maintenance and memory (Oh et al, 2010; Voncken et al, 1998; Voncken et al, 1995). Mice lacking both Bcr and the highly related Rac-GAP Abr (Figure S2A) are more seriously impaired, exhibiting circling behavior, vestibular dysgenesis, cerebellar developmental defects, and abnormal inflammatory responses (Cunnick et al, 2009; Kaartinen et al, 2001; Kaartinen et al, 2002). The more severe phenotypes observed in the Bcr −/− Abr −/− mice suggest that some functions of Bcr and Abr overlap.…”

Role of Rac GTPase activating proteins in regulation of NADPH oxidase in human neutrophils

“…Due to their complex domain structure [32,34] and extensive regulation [30,35], RacGAPs could fine tune Nox activity. In fact, a role for RacGAPs in the regulation of assembly and function of the Nox2 complex has been indicated in previous in vitro studies [36][37][38][39][40] and in genetically modified animals [41][42][43]. These were all isolated studies and comparative aspects have not been raised.…”