Requirement for Vav Proteins in Post-Recruitment Neutrophil Cytotoxicity in IgG but Not Complement C3-Dependent Injury

Utomo, Ahmad; Hirahashi, Junichi; Mekala, Divya; Asano, Kenichi; Glogauer, Michael; Culleré, Xavier; Mayadas, Tanya N.

doi:10.4049/jimmunol.180.9.6279

Cited by 20 publications

(18 citation statements)

References 70 publications

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“…26 Similarly, Vav1 2/2 neutrophils have mildly impaired GPCR-dependent F-actin polymerization and chemotaxis 27 and reduced Mac1-dependent crawling under flow, ) cells adhere and chemotax normally, despite reduced spreading, with attenuated adhesion under flow. 21,23 Consequently, neutrophil recruitment is somewhat reduced in P-Rex1 2/2 mice, but largely normal in Vav1 mice during sterile peritonitis 23 or on immune complex deposition in the skin or lung 29 or in Vav null mice during bacterial lung inflammation.…”

Section: Introductionmentioning

confidence: 99%

P-Rex and Vav Rac-GEFs in platelets control leukocyte recruitment to sites of inflammation

Pan

Amison

Riffo‐Vasquez

et al. 2015

Blood

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Key Points• P-Rex and Vav Rac-GEFs cooperate in leukocyte recruitment during inflammation by facilitating leukocyte adhesion to the vascular endothelium.• P-Rex/Vav expression in platelets is required for vascular adhesion and recruitment of neutrophils and eosinophils into lung tissue.The small GTPase Rac is required for neutrophil recruitment during inflammation, but its guanine-nucleotide exchange factor (GEF) activators seem dispensable for this process, which led us to investigate the possibility of cooperation between Rac-GEF families. Thioglycollate-induced neutrophil recruitment into the peritoneum was more severely impaired in P-Rex1 2/2 Vav1 2/2 (P1V1) or P-Rex1 2/2 Vav3 2/2 (P1V3) mice than in P-Rex null or Vav null mice, suggesting cooperation between P-Rex and Vav Rac-GEFs in this process. Neutrophil transmigration and airway infiltration were all but lost in P1V1 and P1V3 mice during lipopolysaccharide (LPS)-induced pulmonary inflammation, with altered intercellular adhesion molecule 1-dependent slow neutrophil rolling and strongly reduced L-and E-selectin-dependent adhesion in airway postcapillary venules. Analysis of adhesion molecule expression, neutrophil adhesion, spreading, and migration suggested that these defects were only partially neutrophil-intrinsic and were not obviously involving vascular endothelial cells. Instead, P1V1 and P1V3 platelets recapitulated the impairment of LPS-induced intravascular neutrophil adhesion and recruitment, showing P-Rex and Vav expression in platelets to be crucial. Similarly, during ovalbumin-induced allergic inflammation, pulmonary recruitment of P1V1 and P1V3 eosinophils, monocytes, and lymphocytes was compromised in a plateletdependent manner, and airway inflammation was essentially abolished, resulting in improved airway responsiveness. Therefore, platelet P-Rex and Vav family Rac-GEFs play important proinflammatory roles in leukocyte recruitment. (Blood. 2015;125(7):1146-1158) IntroductionDuring inflammation, neutrophils are rapidly recruited from the bloodstream into inflamed tissues where they mount proinflammatory and antimicrobial responses.1 Recruitment occurs in a cascade of steps, beginning with the upregulation of P-selectin on the surface of endothelial cells that line postcapillary venules. P-selectin captures neutrophils from the bloodstream by engaging P-selectin glycoprotein ligand 1 (PSGL1) on their surface, enabling them to roll along the intraluminal wall. When captured, L-selectin on the neutrophil surface engages endothelial PSGL1 to support rolling, and endothelial E-selectin engages neutrophil PSGL1, among other counterligands, to slow rolling down. Binding of the neutrophil integrins LFA1 and Mac1 to their endothelial ligand intercellular adhesion molecule 1 (ICAM1) confers firm adhesion, and Mac1 enables the cells to crawl along the vessel wall before they actively transmigrate into the inflamed tissue by para-or transcellular routes.2 This recruitment cascade has largely been elucidated in the inflamed cremaster muscle and mesen...

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Section: Introductionmentioning

confidence: 99%

P-Rex and Vav Rac-GEFs in platelets control leukocyte recruitment to sites of inflammation

Pan

Amison

Riffo‐Vasquez

et al. 2015

Blood

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“…The predominant isoforms of the Vav family in mouse neutrophils are Vav1 and Vav3 (25). Similarly to P-Rex1, Vav1-deficient neutrophils have reduced GPCR-dependent ROS formation and a minor defect in chemotaxis (26 (27). Thus, Vav family GEFs are important for neutrophil-dependent immune functions and inflammatory conditions in vivo.…”

Section: /Rac2mentioning

confidence: 99%

P-Rex1 and Vav1 Cooperate in the Regulation of Formyl-Methionyl-Leucyl-Phenylalanine–Dependent Neutrophil Responses

Lawson

Donald

Anderson

et al. 2011

The Journal of Immunology

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G protein-coupled receptor (GPCR) activation elicits neutrophil responses such as chemotaxis and reactive oxygen species (ROS) formation, which depend on the small G protein Rac and are essential for host defense. P-Rex and Vav are two families of guanine-nucleotide exchange factors (GEFs) for Rac, which are activated through distinct mechanisms but can both control GPCR-dependent neutrophil responses. It is currently unknown whether they play specific roles or whether they can compensate for each other in controlling these responses. In this study, we have assessed the function of neutrophils from mice deficient in P-Rex and/or Vav family GEFs. We found that both the P-Rex and the Vav family are important for LPS priming of ROS formation, whereas particle-induced ROS responses and cell spreading are controlled by the Vav family alone. Surprisingly, fMLF-stimulated ROS formation, adhesion, and chemotaxis were synergistically controlled by P-Rex1 and Vav1. These responses were more severely impaired in neutrophils lacking both P-Rex1 and Vav1 than those lacking the entire P-Rex family, the entire Vav family, or both P-Rex1 and Vav3. P-Rex1/Vav1 (P1V1) double-deficient cells also showed the strongest reduction in fMLF-stimulated activation of Rac1 and Rac2. This reduction in Rac activity may be sufficient to cause the defects observed in fMLF-stimulated P1V1 neutrophil responses. Additionally, Mac-1 surface expression was reduced in P1V1 cells, which might contribute further to defects in responses involving integrins, such as GPCR-stimulated adhesion and chemotaxis. We conclude that P-Rex1 and Vav1 together are the major fMLFR -dependent Dbl family Rac-GEFs in neutrophils and cooperate in the control of fMLF-stimulated neutrophil responses.

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“…Previous studies have suggested that Mac-1 has contextdependent inhibitory and activating functions for recruitment of leukocytes to the site of inflammation. Mac-1 deficiency resulted in increased Neu accumulation and enhanced tissue injury in mouse models of rheumatoid arthritis, reverse Arthus reaction, and lupus nephritis (13,44,45), but resulted in decreased Neu accumulation and attenuated inflammation in models of acute anti-GBM, thrombotic glomerulonephritis, and bullous pemphigoid (13,46). In the current study, we observed significantly enhanced initial recruitment of Neu and Eos into the peritoneal cavity in Mac-1 mutant animals; however, the kinetics of subsequent accumulation differed in these granulocytes, as Neu generally decreased whereas Eos levels remained high until day 2.…”

Section: /2mentioning

confidence: 99%

Pristane-Induced Granulocyte Recruitment Promotes Phenotypic Conversion of Macrophages and Protects against Diffuse Pulmonary Hemorrhage in Mac-1 Deficiency

Shi

Tsuboi

Furuhashi

et al. 2014

The Journal of Immunology

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Diffuse pulmonary hemorrhage (DPH) is an uncommon but critical complication of systemic lupus erythematosus. Peritoneal administration of 2,6,10,14-tetramethylpentadecane (pristane) can recapitulate a lupus-like syndrome in mice, which can develop into DPH within a few weeks, especially in C57BL/6 mice. Mac-1 (CD11b/CD18), a leukocyte adhesion molecule, is known to play a role in inflammation by regulating migration of leukocytes into injured tissue. In this study, we aimed to clarify the role of Mac-1 in pristane-induced DPH, using Mac-1−/− and wild-type (WT) mice on a C57BL/6 background. After pristane injection, Mac-1−/− mice showed reduced prevalence of DPH and attenuated peritonitis compared with WT mice. Analysis of the peritoneal lavage on days 5 and 10 after pristane treatment revealed increased numbers of eosinophils and alternatively activated macrophages, but decreased numbers of neutrophils and classically activated macrophages in Mac-1−/− mice compared with WT. Enhanced production of IL-4 and IL-13, both key mediators of macrophage polarization toward the mannose receptor+ (MMR+) phenotype, was observed in the peritoneal cavity of Mac-1−/− mice. Depletion of neutrophils and eosinophils or adoptive transfer of classically activated macrophages resulted in the exacerbation of pristane-mediated DPH in both WT and Mac-1−/− mice. Moreover, peritoneal transfer of F4/80highMMR+ alternatively activated macrophages successfully reduced the prevalence of DPH in WT mice. Collectively, Mac-1 promoted acute inflammatory responses in the peritoneal cavity and the lungs by downregulating granulocyte migration and subsequent phenotypic conversion of macrophages in a pristane-induced systemic lupus erythematosus model.

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Requirement for Vav Proteins in Post-Recruitment Neutrophil Cytotoxicity in IgG but Not Complement C3-Dependent Injury

Cited by 20 publications

References 70 publications

P-Rex and Vav Rac-GEFs in platelets control leukocyte recruitment to sites of inflammation

P-Rex and Vav Rac-GEFs in platelets control leukocyte recruitment to sites of inflammation

P-Rex1 and Vav1 Cooperate in the Regulation of Formyl-Methionyl-Leucyl-Phenylalanine–Dependent Neutrophil Responses

Pristane-Induced Granulocyte Recruitment Promotes Phenotypic Conversion of Macrophages and Protects against Diffuse Pulmonary Hemorrhage in Mac-1 Deficiency

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