Antiadhesive properties of biological surfaces are protective against stimulated granulocytes.

Fehr, Jörg; Moser, René; Leppert, David; Groscurth, Peter

doi:10.1172/jci112003

Cited by 62 publications

(28 citation statements)

References 24 publications

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“…The engagement of adhesion receptors induces an initial suppression of ROS formation, resulting in a dramatically delayed oxidative response to a number of stimuli, such as fMLF and TNF-␣ (13,14,37). This delayed response is thought to correspond to the in situ situation, in which inappropriate ROS formation is inhibited to prevent tissue damage when cells are migrating through the tissue to inflammatory sites.…”

Section: Discussionmentioning

confidence: 99%

Critical Role of Proline-Rich Tyrosine Kinase 2 in Reversion of the Adhesion-Mediated Suppression of Reactive Oxygen Species Generation by Human Neutrophils

Zhao

Bokoch

2005

The Journal of Immunology

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Neutrophils act as the first line of innate immune defense against invading microorganisms during infection and inflammation. The tightly regulated production of reactive oxygen species (ROS) through activation of NADPH oxidase is a major weapon used by neutrophils and other phagocytic leukocytes to combat such pathogens. Cellular adhesion signals play important physiological roles in regulating the activation of NADPH oxidase and subsequent ROS formation. We previously showed that the initial suppression of the oxidase response of chemoattractant-stimulated adherent neutrophils is mediated via inhibition of Vav1-induced activation of the NADPH oxidase regulatory GTPase Rac2 by adhesion signals. In this study we show that prior exposure of neutrophils to a number of cytokines and inflammatory mediators, including TNF-α, GM-CSF, and platelet-activating factor, overcomes the adhesion-mediated suppression of ROS formation. Proline-rich tyrosine kinase 2 (pyk2) activity is enhanced under these conditions, correlating with the restoration of Vav1 and Rac2 activities. Both dominant negative pyk2 and a pyk2-selective inhibitor prevented restoration of ROS production induced by TNF-α, GM-CSF, and platelet-activating factor, and this loss of pyk2 activity resulted in decreased Vav1 tyrosine phosphorylation and subsequent Rac2 activation. Our studies identify pyk2 as a critical regulatory component and a molecular switch to overcome the suppression of leukocyte oxidant generation by cell adhesion. This activity constitutes a mechanism by which cytokines might lead to rapid elimination of invading pathogens by adherent neutrophils under normal conditions or enhance tissue damage in pathological states.

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Section: Discussionmentioning

confidence: 99%

Critical Role of Proline-Rich Tyrosine Kinase 2 in Reversion of the Adhesion-Mediated Suppression of Reactive Oxygen Species Generation by Human Neutrophils

Zhao

Bokoch

2005

The Journal of Immunology

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“…Evidence that engagement of adhesion receptors can induce a suppression of ROS generation was first provided by Fehr et al (33) and Nathan (3). Nathan showed that adhesion of neutrophils to surfaces coated with ECM proteins (fibronectin, fibrinogen, laminin, and the like) resulted in a dramatically delayed oxidative response to soluble cytokine stimuli (fMLF, TNF-α, and so on).…”

Section: Discussionmentioning

confidence: 99%

The molecular basis for adhesion-mediated suppression of reactive oxygen species generation by human neutrophils

Zhao¹,

Benard²,

Bohl³

et al. 2003

J. Clin. Invest.

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Human neutrophil adherence to ECMs induces an initial inhibition of stimulated reactive oxygen species (ROS) formation, followed by an enhanced phase of oxidant production. The initial integrin-mediated suppression of ROS constitutes a mechanism to prevent inappropriate tissue damage as leukocytes migrate to inflammatory sites. The Rac2 guanosine 5′-triphosphatase (GTPase) is a critical regulatory component of the phagocyte NADPH oxidase. We show that activation of Rac2 is inhibited in adherent neutrophils, correlating with inhibition of ROS formation. Conversely, NADPH oxidase components p47 and p67 assemble normally, suggesting a specific action of adhesion on the Rac2 molecular switch. Reconstitution with activated Rac2 restored rapid NADPH oxidase activation kinetics to adherent neutrophils, establishing that inhibition was due to defective Rac2 activity. We provide evidence that integrins inhibit Rac2 activation via a membrane-associated guanine nucleotide exchange factor, likely to be Vav1. Activation of Vav1, but not its upstream activator, Syk, is suppressed by cell adhesion. Vav1 activity is inhibited due to dephosphorylation of the regulatory Tyr174 via enhanced tyrosine phosphatase activity in adherent cells. These studies identify an integrin-mediated pathway in which Vav1 is as a strong candidate for the critical regulatory point in suppression of Rac2 activation and ROS generation during inflammatory responses

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“…These conditions bear little resemblance to the stages of inflammation in which PMN stick to endothelium, penetrate basement membranes and migrate through tissues, adherent the whole while to other types ofcells and/or proteins of extracellular matrix. Attempts to analyze the respiratory burst of adherent PMN have been thwarted by the propensity of nonbiologic surfaces to trigger the burst (6), and of biologic surfaces to suppress it (22).…”

Section: Introductionmentioning

confidence: 99%

Neutrophil activation on biological surfaces. Massive secretion of hydrogen peroxide in response to products of macrophages and lymphocytes.

1987

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Recombinant tumor necrosis factor alpha (rTNFa) and beta (rTNF#) did not trigger H202 release from PMN in suspension. However, when PMN were plated on polystyrene surfaces coated with serum, fibronectin, vitronectin, laminin, or human umbilical vein endothelial cells (HUVEC), rTNFs induced a massive, prolonged secretory response, similar to that elicited by phorbol myristate acetate (PMA) or bacteria. On serum-coated plates, the maximum sustained rate of H202 release in response to rTNFa was 2.6±0.2 nmol/min per 106 PMN, the same as that with PMA; release continued for 73±4 min. On laminin-coated surfaces or HUVEC, release of H202 in response to rTNFs was slower, but lasted 3.5 h, reaching the same total (> 100 nmol/106 PMN). Not only was this response far longer and larger than for other soluble stimuli of the respiratory burst studied with PMN in suspension, but the concentration necessary to elicit a half-maximal response (EC50) for rTNFa was orders of magnitude lower (55 pM).Responses were similar with FMLP, but ranged from zero to small with recombinant IFNa, recombinant IFN#,, recombinant IFN'y, platelet-derived growth factor, recombinant IL-1#, or bacterial lipopolysaccharide. Adherent monocytes did not secrete H202 in response to rTNFs. H202 secretion by adherent PMN was first detectable 15-90 min after addition of rTNFs or FMLP. This lag period was unaffected by prior exposure of PMN to rTNFa in suspension, by allowing PMN to adhere before adding rTNFa, or by incubating adherent PMN in medium conditioned by rTNFa-treated PMN. Cytochalasins abolished H202 secretion in response to rTNFs, but not FMLP, if added during, but not after, the lag period. Thus, H202 secretion from rTNFa-treated PMN appears to be a direct but delayed response that requires assembly of microfilaments during exposure to the cytokine. These results suggest that PMN adherent to intra-or extravascular surfaces may undergo a massive, prolonged respiratory burst at the command of macrophages and lymphocytes reacting to microbial products and antigens.

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Antiadhesive properties of biological surfaces are protective against stimulated granulocytes.

Cited by 62 publications

References 24 publications

Critical Role of Proline-Rich Tyrosine Kinase 2 in Reversion of the Adhesion-Mediated Suppression of Reactive Oxygen Species Generation by Human Neutrophils

Critical Role of Proline-Rich Tyrosine Kinase 2 in Reversion of the Adhesion-Mediated Suppression of Reactive Oxygen Species Generation by Human Neutrophils

The molecular basis for adhesion-mediated suppression of reactive oxygen species generation by human neutrophils

Neutrophil activation on biological surfaces. Massive secretion of hydrogen peroxide in response to products of macrophages and lymphocytes.

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