Preliminary evidence for a matrix metalloproteinase-2 (MMP-2)-dependent shedding of soluble CD40 ligand (sCD40L) from activated platelets

Reinboldt, Stephan; Wenzel, Folker; Rauch, Bernhard; Hohlfeld, Thomas; Grandoch, Maria; Fischer, Jens W.; Weber, Artur‐Aron

doi:10.1080/09537100903096684

Cited by 31 publications

(24 citation statements)

References 28 publications

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“…10,40 Notably, it was observed that administration of NSC23766 significantly decreased the sepsis-induced increase of MMP-9 levels in plasma, indicating that Rac1 might be an important regulator of systemic levels of MMP-9 in abdominal sepsis. It should be mentioned that two studies have reported that MMP-2 might promote platelet release of CD40L in vitro, 41,42 but levels of MMP-2 in the plasma are not elevated in abdominal sepsis. 10 The potential presence of MMP-9 in platelets has been a controversial subject in the literature.…”

Section: Discussionmentioning

confidence: 99%

Rac1 regulates platelet shedding of CD40L in abdominal sepsis

Hwaiz

Rahman

Zhang

et al. 2014

Laboratory Investigation

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Matrix metalloproteinase-9 (MMP-9) regulates platelet shedding of CD40L in abdominal sepsis. However, the signaling mechanisms controlling sepsis-induced shedding of CD40L from activated platelets remain elusive. Rac1 has been reported to regulate diverse functions in platelets; we hypothesized herein that Rac1 might regulate platelet shedding of CD40L in sepsis. The specific Rac1 inhibitor NSC23766 (N6-[2-[[4-(diethylamino)-1-methylbutyl] amino]-6-methyl-4-pyrimidinyl]-2 methyl-4, 6-quinolinediamine trihydrochloride) was administered to mice undergoing cecal ligation and puncture (CLP). Levels of CD40L and MMP-9 in plasma, platelets, and neutrophils were determined by use of ELISA, western blot, and confocal microscopy. Platelet depletion abolished the CLP-induced increase in plasma levels of CD40L. Rac1 activity was significantly increased in platelets from septic animals. Administration of NSC23766 abolished the CLP-induced enhancement of soluble CD40L levels in the plasma. Moreover, Rac1 inhibition completely inhibited proteinase-activated receptor-4-induced surface mobilization and secretion of CD40L in isolated platelets. CLP significantly increased plasma levels of MMP-9 and Rac1 activity in neutrophils. Treatment with NSC23766 markedly attenuated MMP-9 levels in the plasma from septic mice. In addition, Rac1 inhibition abolished chemokine-induced secretion of MMP-9 from isolated neutrophils. Finally, platelet shedding of CD40L was significantly reduced in response to stimulation with supernatants from activated MMP-9-deficient neutrophils compared with supernatants from wild-type neutrophils, indicating a direct role of neutrophil-derived MMP-9 in regulating platelet shedding of CD40L. Our novel data suggest that sepsis-induced platelet shedding of CD40L is dependent on Rac1 signaling. Rac1 controls surface mobilization of CD40L on activated platelets and MMP-9 secretion from neutrophils. Thus, our findings indicate that targeting Rac1 signaling might be a useful way to control pathologic elevations of CD40L in the systemic circulation in abdominal sepsis.

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Section: Discussionmentioning

confidence: 99%

Rac1 regulates platelet shedding of CD40L in abdominal sepsis

Hwaiz

Rahman

Zhang

et al. 2014

Laboratory Investigation

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“…It should be mentioned that these findings do not exclude the possibility that other MMPs or proteases might also be involved in the regulation of platelet shedding of CD40L in sepsis. For example, two in vitro studies have reported that MMP-2 might promote platelet release of CD40L in vitro [18,42].…”

Section: Discussionmentioning

confidence: 99%

“…Matrix metalloproteinases (MMPs) constitute a large family of more than 25 functionally related endopeptidases [15] with the capacity to cleave most matrix proteins as well as several non-matrix targets, including cytokines, chemokines, adhesion molecules, and surface receptors [16]. One study reported that inhibitors of glycoprotein IIb-IIIa inhibit release of sCD40L from activated platelets [17], whereas other investigators found that inhibition of MMP-2 [18] and MMP-9 [19] decreased platelet shedding of CD40L. In this context, it is interesting to note that previous studies have found that the levels of certain MMPs, in particular members of the gelatinase subfamily (MMP-2 and MMP-9), are elevated in the plasma of septic patients [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Platelet shedding of CD40L is regulated by matrix metalloproteinase‐9 in abdominal sepsis

Rahman

Zhang

Chew

et al. 2013

Journal of Thrombosis and Haemostasis

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To cite this article: Rahman M, Zhang S, Chew M, Syk I, Jeppsson B, Thorlacius H. Platelet shedding of CD40L is regulated by matrix metalloproteinase-9 in abdominal sepsis. J Thromb Haemost 2013; 11: 1385-98.Summary. Background and objectives: Platelet-derived CD40L is known to regulate neutrophil recruitment and lung damage in sepsis. However, the mechanism regulating shedding of CD40L from activated platelets is not known. We hypothesized that matrix metalloproteinase (MMP)-9 might cleave surface-expressed CD40L and regulate pulmonary accumulation of neutrophils in sepsis. Methods: Abdominal sepsis was induced by cecal ligation and puncture (CLP) in wild-type and MMP-9-deficient mice. Edema formation, CXC chemokine levels, myeloperoxidase levels, neutrophils in the lung and plasma levels of CD40L and MMP-9 were quantified. Results: CLP increased plasma levels of MMP-9 but not MMP-2. The CLP-induced decrease in platelet surface CD40L and increase in soluble CD40L levels were significantly attenuated in MMP-9 gene-deficient mice. Moreover, pulmonary myeloperoxidase (MPO) activity and neutrophil infiltration in the alveolar space, as well as edema formation and lung injury, were markedly decreased in septic mice lacking MMP-9. In vitro studies revealed that inhibition of MMP-9 decreased platelet shedding of CD40L. Moreover, recombinant MMP-9 was capable of cleaving surface-expressed CD40L on activated platelets. In human studies, plasma levels of MMP-9 were significantly increased in patients with septic shock as compared with healthy controls, although MMP-9 levels did not correlate with organ injury score. Conclusions: Our novel data propose a role of MMP-9 in regulating platelet-dependent infiltration of neutrophils and tissue damage in septic lung injury by controlling CD40L shedding from platelets. We conclude that targeting MMP-9 may be a useful strategy to limit acute lung injury in abdominal sepsis.

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“…The enzyme responsible for CD154 shedding on the surface of activated platelets has been demonstrated previously (8), but little is known about this process regarding T-cells. The metalloproteinase ADAM10 has been highlighted as a possible candidate (13), albeit no direct demonstration of its implication in CD154 cleavage has been provided.…”

Section: Cd154 Shedding Is Mediated By Adam10 and Adam17-mentioning

confidence: 99%

“…Interestingly, the shedding of CD154 from platelets is triggered following its interaction with CD40, which is also expressed on platelets (7). Recent evidence supports the role of matrix metalloproteinase-2 (MMP-2) (8), in association with the ␣IIb␤3 integrin (9), in mediating the proteolytic cleavage of CD154 from activated platelets. Moreover, MMP-9 was also reported to be involved in the shedding of CD154 from platelets with Crohn disease.…”

mentioning

confidence: 99%

CD154 Is Released from T-cells by a Disintegrin and Metalloproteinase Domain-containing Protein 10 (ADAM10) and ADAM17 in a CD40 Protein-dependent Manner

Yacoub¹,

Benslimane²,

Al-Zoobi

et al. 2013

Journal of Biological Chemistry

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Background: CD154 is released from T-cells in a manner that remains elusive. Results: CD154 is released from Jurkat E6.1 T-cells by ADAM10 and ADAM17 upon its interaction with CD40 exclusively. Conclusion: The cleavage of CD154 is mediated through specific signaling events that bypass many other CD154 signaling events. Significance: These data may lead to the generation of novel targets for the treatment of CD154-associated disorders.

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Preliminary evidence for a matrix metalloproteinase-2 (MMP-2)-dependent shedding of soluble CD40 ligand (sCD40L) from activated platelets

Cited by 31 publications

References 28 publications

Rac1 regulates platelet shedding of CD40L in abdominal sepsis

Rac1 regulates platelet shedding of CD40L in abdominal sepsis

Platelet shedding of CD40L is regulated by matrix metalloproteinase‐9 in abdominal sepsis

CD154 Is Released from T-cells by a Disintegrin and Metalloproteinase Domain-containing Protein 10 (ADAM10) and ADAM17 in a CD40 Protein-dependent Manner

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