Platelet-Dependent Neutrophil Function Is Dysregulated by M Protein from Streptococcus pyogenes

Hurley, Sinead; Kahn, Fredrik; Nordenfelt, Pontus; Mörgelin, Matthias; Sørensen, Ole E.; Shannon, Oonagh

doi:10.1128/iai.00508-15

Cited by 28 publications

(27 citation statements)

References 42 publications

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“…This highlights a platelet‐dependent pathway that modulates neutrophil activation in the context of sepsis, which is a potent source of TLR‐triggering molecules. Hurley et al 24. demonstrated that, in response to Streptococcus pyogenes M1 protein (another TLR‐triggering molecule), platelet–neutrophil complexes formed in cell culture and, interestingly, these complexes exhibited reduced chemotaxis and bacterial killing.…”

Section: Discussionmentioning

confidence: 99%

“…Hurley et al 24 demonstrated that, in response to Streptococcus pyogenes M1 protein (another TLR-triggering molecule), platelet-neutrophil complexes formed in cell culture and, interestingly, these complexes exhibited reduced chemotaxis and All leucocyte-only measurements (À platelets) were normalised to 1, and all coculture (+ platelets) measurements were compared to this normalised response. Differences between these measurements were examined by paired t-tests.…”

Section: Discussionmentioning

confidence: 99%

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Platelets regulate leucocyte responses to Toll‐like receptor stimulation

et al. 2018

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ObjectivesPlatelets are important regulators of vascular thrombosis and inflammation and are known to express Toll‐like receptors (TLRs). Through TLRs, platelets mediate a number of responses by interacting with leucocytes. Here, we report the extent to which platelets modulate in vitro peripheral blood mononuclear cells (PBMCs) and granulocyte responses to TLR4, TLR2/1 and TLR2/6 stimulation in healthy subjects.MethodsPeripheral blood mononuclear cells and granulocytes from 10 healthy volunteers were cultured alone or cocultured with platelets. Cultures were left unstimulated or stimulated with 1 or 100 ng mL−1 of either LPS (TLR4 agonist), Pam3CSK4 (TLR2/1 agonist) or fibroblast‐stimulating lipopeptide (FSL)‐1 (TLR2/6 agonist). Neutrophil activation (CD66b expression), monocyte activation (HLA‐DR), granulocyte elastase production and PBMC cytokine and chemokine production were examined.ResultsPlatelet coculture decreased neutrophil CD66b expression in response to LPS, Pam3CSK4 and FSL‐1, and modestly decreased monocyte HLA‐DR expression in response to low‐dose LPS. Platelets reduced granulocyte elastase secretion in response to low doses of all TLR agonists tested. In response to LPS, platelet coculture reduced IL‐6, tumor necrosis factor (TNF)‐α and MIP‐1β production, and increased IL‐10 production by PBMCs. In response to FSL‐1, platelets increased IL‐6, IL‐10 and MIP‐1β production, but reduced TNF‐α production. Platelet coculture did not alter PBMC cytokine/chemokine production in response to Pam3CSK4.ConclusionThis study challenges the notion that platelets act solely in a pro‐inflammatory manner. Rather, platelets are complex immunomodulators that regulate leucocyte responses to TLR stimulation in a TLR agonist‐specific manner. Platelets may modulate leucocyte responses to dampen inflammation, and this platelet effect may play an important role in reducing inflammation‐mediated host damage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Platelets regulate leucocyte responses to Toll‐like receptor stimulation

et al. 2018

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“…S. pyogenes, for example, induces large, fibrinogen-associated platelet-neutrophil complexes, which reduce neutrophil chemotaxis and phagocytosis, thus supporting bacterial survival [33]. Staphylococcus aureus α-toxin binds to platelet Adisintegrin-and-metalloproteinase-domain-containing-protein-10 (ADAM10) leading to proteolysis of the collagen receptor GPVI.…”

Section: Phagocytosis Neutrophil Extracellular Trap Formation and Bamentioning

confidence: 99%

Platelet Interaction with Innate Immune Cells

Kral¹,

Schrottmaier²,

Salzmann³

et al. 2016

Transfus Med Hemother

220

182

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Platelets are key players in haemostasis and prevent excessive bleeding upon injury. In response to vessel damage, platelets adhere and get activated at sites of injury, leading to recruitment of further platelets and thrombus formation. As injury represents a risk for infection, platelets recruit and activate leukocytes via direct cell-cell contacts and indirectly via cytokines and platelet-derived microvesicles. Activated platelets directly interact with leukocytes via P-selectin (CD62P) interaction with P-selectin glycoprotein ligand 1 (PSGL-1). This initial binding is enhanced by interaction of various other receptors, depending on the leukocyte subtype, leading to mutual activation and local cytokine release (reviewed in [1]), which modulates immune responses.Upon activation platelets release a variety of α-granule-derived cytokines, chemokines and growth factors [2]. The mechanism of packaging inflammatory cargo into α-granules, however, is incompletely understood [3]. Cytokines can be packaged into granules during megakaryopoiesis [4] either via biosynthesis in the megakaryocyte (e.g. platelet factor 4/CXCL4) or via endocytosis from the microenvironment (e.g. albumin) in the bone marrow [3]. Despite lacking a nucleus, platelets can splice and de novo synthesise proteins from megakaryocyte-derived (pre)mRNA as shown for 6]. Via their open canalicular system platelets also take up factors from the circulation. Further platelets can fuse with microvesicles, which leads to intercellular exchanges of chemotactic receptors such as C-C chemokine receptor type 5 (CCR5) and chemokine (C-X-C motif) receptor 4 (CXCR4) [7,8]. Platelet cytokine levels have been demonstrated to be elevated in cancer patients [9,10], indicating either an active uptake of these factors by platelets or disease-related changes in megakaryopoiesis. This suggests that underlying pathologies might influence not only platelet reactivity but also their potential to modulate immune responses. KeywordsPlatelets · Platelet-leukocyte aggregates · P-selectin · Inflammation · Infection · Cardiovascular disease SummaryBeyond their traditional role in haemostasis and thrombosis, platelets are increasingly recognised as immune modulatory cells. Activated platelets and platelet-derived microparticles can bind to leukocytes, which stimulates mutual activation and results in rapid, local release of platelet-derived cytokines. Thereby platelets modulate leukocyte effector functions and contribute to inflammatory and immune responses to injury or infection. Platelets enhance leukocyte extravasation, differentiation and cytokine release. Platelet-neutrophil interactions boost oxidative burst, neutrophil extracellular trap formation and phagocytosis and play an important role in host defence. Platelet interactions with monocytes propagate their differentiation into macrophages, modulate cytokine release and attenuate macrophage functions. Depending on the underlying pathology, platelets can enhance or diminish leukocyte cytokine production, indicating that pla...

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“…We have previously demonstrated that the released M1 protein of the S. pyogenes emm1 serotype can mediate platelet activation (21), platelet/leukocyte complex formation, and modulation of the inflammatory response of neutrophils (22). Platelet activation by M1 protein is dependent on binding of M1 protein together with plasma fibrinogen and specific anti-M1 IgG to the fibrinogen receptor and Fc receptor on the platelet surface (11).…”

mentioning

confidence: 99%

Complement Activation Occurs at the Surface of Platelets Activated by Streptococcal M1 Protein and This Results in Phagocytosis of Platelets

Palm

Sjöholm

Malmström

et al. 2019

The Journal of Immunology

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Platelets circulate the bloodstream and principally maintain hemostasis. Disturbed hemostasis, a dysregulated inflammatory state, and a decreased platelet count are all hallmarks of severe invasive Streptococcus pyogenes infection, sepsis. We have previously demonstrated that the released M1 protein from S. pyogenes activates platelets, and this activation is dependent on the binding of M1 protein, fibrinogen, and M1-specific IgG to platelets in susceptible donors. In this study, we characterize the M1-associated protein interactions in human plasma and investigate the acquisition of proteins to the surface of activated platelets and the consequences for platelet immune function. Using quantitative mass spectrometry, M1 protein was determined to form a protein complex in plasma with statistically significant enrichment of fibrinogen, IgG3, and complement components, especially C1q. Using flow cytometry, these plasma proteins were also confirmed to be acquired to the platelet surface, resulting in complement activation on M1-activated human platelets. Furthermore, we demonstrated an increased phagocytosis of M1-activated platelets by monocytes, which was not observed with other physiological platelet agonists. This reveals a novel mechanism of complement activation during streptococcal sepsis, which contributes to the platelet consumption that occurs in sepsis.

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Platelet-Dependent Neutrophil Function Is Dysregulated by M Protein from Streptococcus pyogenes

Cited by 28 publications

References 42 publications

Platelets regulate leucocyte responses to Toll‐like receptor stimulation

Platelets regulate leucocyte responses to Toll‐like receptor stimulation

Platelet Interaction with Innate Immune Cells

Complement Activation Occurs at the Surface of Platelets Activated by Streptococcal M1 Protein and This Results in Phagocytosis of Platelets

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