Platelet and soluble CD40L in meningococcal sepsis

Inwald, David; Faust, Saul N; Lister, Paula; Peters, Mark; Levin, Michael; Heyderman, Robert S.; Klein, Nigel

doi:10.1007/s00134-006-0250-2

Cited by 34 publications

(23 citation statements)

References 30 publications

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“…We have demonstrated that this platelet-dependent pulmonary accumulation of neutrophils is mediated by sCD40L released from platelets in abdominal sepsis [9]. In support of a role of CD40L in sepsis, recent studies have shown that plasma levels of sCD40L are elevated in patients with sepsis, and that platelet shedding of CD40L is regulated by MMPs [25,35,36]. However, the specific mechanism regulating platelet shedding of CD40L in sepsis is not known.…”

Section: Discussionmentioning

confidence: 93%

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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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Section: Discussionmentioning

confidence: 93%

“…2A). In parallel, surface expression of CD40L on platelets decreased; that is, the mean fluorescence intensity was 49 (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55) in sham mice and 32 (29)(30)(31)(32)(33)(34)(35)(36) in septic WT mice (Fig. 2B).…”

mentioning

confidence: 91%

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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“…8 In support of a role of CD40L in sepsis, elevated plasma levels of soluble CD40L have been observed in patients with sepsis. 33,34 However, the specific signaling mechanisms regulating platelet shedding of CD40L in sepsis are not known. In the present study, we found that Rac1 activity was increased in platelets from septic mice.…”

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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“…The sparse literature on the levels of CD40L in the plasma from critically ill patients is contradictory. Kälsch et al [12] showed that administration of endotoxin to healthy individuals had no effect of sCD40L levels, whereas another study reported that sCD40L is elevated in children with meningococcal septicemia [13]. However, sCD40L levels in patients with systemic inflammatory response syndrome (SIRS) and in mixed groups of adult sepsis patients have not been studied.…”

Section: Introductionmentioning

confidence: 94%