Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III

Bergmeier, Wolfgang; Goerge, Tobias; Wang, Hong Wei; Crittenden, Jill R.; Baldwin, A.; Cifuni, Stephen M.; Housman, David E.; Graybiel, Ann M.; Wagner, Denisa D.

doi:10.1172/jci30575

Cited by 174 publications

(182 citation statements)

References 57 publications

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“…GTPases in turn are activated by guanine nucleotide exchange factors (GEFs). In neutrophils stimulated with leukotriene B 4 , Rap1 is activated by CalDAG-GEFI, which is activated by Ca 2+ and DAG, two products of PLC (39). In contrast, another study using fMLP stimulation revealed that the GEFs Vav1 and PRex1 redundantly mediate the activity of the GTPase Rac (40), suggesting that the different stimuli activate distinctly different pathways.…”

Section: Leukocyte Recruitmentmentioning

confidence: 99%

Integrin Regulation during Leukocyte Recruitment

Herter

Zarbock

2013

The Journal of Immunology

170

138

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Integrins are recognized as vital players in leukocyte recruitment. Integrin malfunction causes severe disease patterns characterized by the inability to fight pathogens. Although inflammatory reactions are beneficial and necessary for host defense, these reactions have to be controlled to prevent tissue destruction and harmful sequelae. In this review, we discuss the different signaling pathways leading to the change of integrin adhesiveness in neutrophils, monocytes, and lymphocytes. We thereby focus on the importance of integrin activation for the different steps of the leukocyte recruitment cascade, including rolling, adhesion, postadhesion strengthening, intravascular crawling, and transmigration, as each step necessitates the proper functioning of a distinct set of integrin molecules that has to be activated specifically. Additionally, we discuss endogenous mechanisms that balance and counteract integrin activation and limit leukocyte recruitment at the site of inflammation. Further insight into these complex mechanisms may provide new approaches for developing new anti-inflammatory therapies.

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Section: Leukocyte Recruitmentmentioning

confidence: 99%

Integrin Regulation during Leukocyte Recruitment

Herter

Zarbock

2013

The Journal of Immunology

170

138

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“…2). Rasgrp2 -/-mice have impaired integrinmediated adhesion in platelets and neutrophils and are considered to be a model for human LAD-III (Bergmeier et al, 2007;Crittenden et al, 2004). This might be so because several LAD-III patients have a mutation in CalDAG-GEF1 that has been reported to affect splicing (Pasvolsky et al, 2007).…”

Section: Activation Of Integrins By Inside-out Signallingmentioning

confidence: 99%

“…Both talin and kindlin-3 have similar FERM (protein 4.1, ezrin, radixin and moesin) domains that bind the β-subunit of integrins at the two NPxY sites (in which x denotes any amino acid) -talin at the membrane-proximal site and kindlin-3 at the membrane-distal site (Ma et al, 2008;Moser et al, 2008). Kindlin-3 knockout (Fermt3 -/-) mice have severe bleeding problems (Moser et al, 2008) similar to the Rasgrp2 -/-mice (Bergmeier et al, 2007;Crittenden et al, 2004), suggesting that kindlin-3 is also a candidate gene involved in LAD-III.…”

Section: +mentioning

confidence: 99%

Integrins in immunity

Evans

Patzak

Svensson

et al. 2009

Journal of Cell Science

264

261

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A successful immune response depends on the capacity of immune cells to travel from one location in the body to another–these cells are rapid migrators, travelling at speeds of μm/minute. Their ability to penetrate into tissues and to make contacts with other cells depends chiefly on the β2 integrin known as LFA-1. For this reason, we describe the control of its activity in some detail. For the non-immunologist, the fine details of an immune response often seem difficult to fathom. However, the behaviour of immune cells, known as leukocytes (Box 1), is subject to the same biological rules as many other cell types, and this holds true particularly for the functioning of the integrins on these cells. In this Commentary, we highlight, from a cell-biology point of view, the integrin-mediated immune-cell migration and cell-cell interactions that occur during the course of an immune response.

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“…Rap isoforms regulate adhesion-dependent processes by modulating integrin affinity and avidity. 2 Loss of leukocyte Rap1 activation is a cause of LAD-III, 3,4 demonstrating the crucial role of this small GTPase in neutrophil control. Agonist-activated PI3Ks generate on activation the lipid second messengers phosphatidylinositol-(3,4,5)-trisphosphate [PtdIns(3,4,5)P 3 ] and PtdIns(3,4)P 2 .…”

mentioning

confidence: 99%

The GTPase-activating protein ARAP3 regulates chemotaxis and adhesion-dependent processes in neutrophils

Gambardella

Anderson

Nußbaum

et al. 2011

Blood

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IntroductionNeutrophils are an essential component of the innate immune responses to invading pathogens and tissue damage. In response to inflammatory stimuli, neutrophils are recruited from the bloodstream to infected tissues, where they produce reactive oxygen species (ROS) and phagocytose and kill pathogens. 1 It is vital that the neutrophil response to inflammatory stimuli is well controlled. Leukocyte adhesion deficiency (LAD) patients, in whom the recruitment process is impaired, suffer from repeated, severe bacterial infections. Conversely, excessive neutrophil responsiveness is also detrimental, causing tissue damage and inflammation, as exemplified in autoimmune diseases.Work aimed at identifying the molecular machinery controlling neutrophils has identified important regulatory players. Rap isoforms regulate adhesion-dependent processes by modulating integrin affinity and avidity. 2 Loss of leukocyte Rap1 activation is a cause of LAD-III, 3,4 demonstrating the crucial role of this small GTPase in neutrophil control. Agonist-activated PI3Ks generate on activation the lipid second messengers phosphatidylinositol-(3,4,5)-trisphosphate [PtdIns(3,4,5)P 3 ] and PtdIns(3,4)P 2 . These cause plasma membrane recruitment and activation of PI3K effectors, which regulate multiple enzymes and pathways. 5 Known PI3K effectors include regulators of Rho and Arf family small GTPases, GTPase-activating proteins (GAPs), and guanine nucleotide exchange factors. Rho family small GTPases are involved in regulating the neutrophil NADPH oxidase and chemotaxis, 6,7 whereas Arf family members regulate phagocytosis, ROS production, and chemotaxis. 8,9 ARAP3 was identified from porcine neutrophils in a screen for PtdIns(3,4,5)P 3 -binding proteins. In vitro, ARAP3 is a PtdIns(3,4,5)P 3 -dependent Arf6 GAP and a Rap-activated RhoA GAP. In addition, in vivo, PtdIns(3,4,5)P 3 drives the recruitment of ARAP3 to the plasma membrane, bringing it into the vicinity of its activator, Rap-GTP, and its substrates, RhoA-GTP and Arf6-GTP. 10,11 The remaining ARAP family members (ARAP1/2) share ARAP3's multidomain structure. 12,13 We sought to identify ARAP3's physiologic function in neutrophils. Using neutrophils from a conditional Arap3 Ϫ/Ϫ mouse model in biologic assays, we demonstrate that ARAP3 regulates adhesion-dependent processes. Loss of ARAP3 causes the preactivation of neutrophil ␤2 integrins and hyperresponsiveness in adhesion-dependent situations, feeding into several biologic responses such as adhesion-dependent ROS formation, granule release, and chemotaxis. Whereas Rap activity was not affected by the loss of ARAP3, RhoA activation was increased in an adhesion-dependent setting, suggesting a role for ARAP3 downstream of Rap in neutrophils. Our results suggest a modulatory role for ARAP3 in neutrophils, which prevents their activation in inappropriate situations. MethodsUnless otherwise stated, materials were obtained from Sigma-Aldrich. Inducible Arap3 ؊/؊ mouse modelGeneration of the Arap3 fl/fl mouse has been described previo...

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Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III

Cited by 174 publications

References 57 publications

Integrin Regulation during Leukocyte Recruitment

Integrin Regulation during Leukocyte Recruitment

Integrins in immunity

The GTPase-activating protein ARAP3 regulates chemotaxis and adhesion-dependent processes in neutrophils

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