Streptococcus sanguinis‐induced cytokine release from platelets

Abstract

Summary. Background: There is increasing evidence that both chronic and acute infections play a role in the development and progression of atherothrombotic disorders. One potential mechanism is the direct activation of platelets by bacteria. A wide range of bacterial species activate platelets through heterogeneous mechanisms. The oral micro-organism S. sanguinis stimulates platelet aggregation in vitro in a strain-dependent manner, although there are no reports of associated cytokine production. Objective: The aim of the present study was to determine whether platelet activation by S. sanguinis involved the release of pro-inflammatory and immune modulating factors, and whether activation was enhanced by epinephrine. Methods and results: Four strains of S. sanguinis and one of S. gordonii stimulated the release of RANTES, PF4, sCD40L and PDGF-AB, whereas only one S. sanguinis strain caused the release of sCD62p. Epinephrine enhanced S. sanguinis-induced platelet aggregation and phosphorylation of phospholipase Cc2 and Erk, but inhibited RANTES, PF4, sCD40L and PDGF-AB release. Wortmannin inhibited S. sanguinis-induced aggregation and release; however, only aggregation was partially reversed by epinephrine. Conclusions: The present study demonstrates that platelets respond to S. sanguinis with both prothrombotic and pro-inflammatory/immune-modulating responses. Epinephrine, potentially released in response to infection and/or stress, can significantly enhance the prothrombotic response, thereby providing a putative link between bacteraemia and acute coronary events during stress. In contrast, epinephrine inhibited the pro-inflammatory/immune-modulating response by an undetermined mechanism.

Platelets and Infections – Complex Interactions with Bacteria

“…CD62P is only released in the presence of one strain of S. sanguinis (82). Another study had also shown that platelets were capable of releasing soluble CD40L (sCD40L) and RANTES after stimulation with IgG-bead complexes, with the absence of aggregation and a very weak expression of CD62P (72).…”

“…The mechanism of inhibition used is unknown but could be linked to the activation of type 3 nitric oxide synthase (NOS) after involvement of the β 2 adrenoreceptors; the resultant generation of nitric oxide (NO) and cGMP has already been described in platelet activation inhibition (82). This clearly demonstrates that platelet aggregation and exocytosis of immunomodulating molecules are two independent functions.…”

Platelet-Bacterial Interactions in the Pathogenesis of Infective Endocarditis — Part I: The Streptococcus

“…For S. sanguinis 2017-78 cytokine secretion was independent of thromboxane production and aggregation. Interestingly this secretion response was inhibited by low doses of epinephrine while aggregation and protein phosphorylation cascades mentioned previously were enhanced [99]. The inhibition of platelet activation by epinephrine has not been noted in response to any other platelet agonists and adds another layer of complexity to bacterial induced platelet activation.…”

“…They examined platelet secretion of soluble inflammatory mediators (Platelet factor 4, RANTES, sCD40L, platelet derived growth factor) in response to a number of S. sanguinis and S. gordonii strains and paired these with their platelet aggregation responses. All strains triggered secretion of cytokines irrespective of the platelet aggregation response but only 1 strain (S. sanguinis 2017-78) triggered release of sCD62p [99]. For S. sanguinis 2017-78 cytokine secretion was independent of thromboxane production and aggregation.…”

“…The dephosphorylation phase is proposed to be due to the activity of platelet endothelial cell adhesion molecule-1 (PECAM-1), an ITIM containing receptor which recruits the tyrosine phosphatase SHP-1 during the lag phase [97]. Further studies by McNicol et al highlighted a role for PI3 kinase mediated phosphorylation of Erk in response to S. sanguinis 2017-78 [99]. PI3 kinase is found downstream of FcγRIIA and GPIb and upstream of the GTPase Rap1b, critical for αIIbβ3 activation [100,101].…”