Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietin

Autores
D'Atri, Lina Paola; Rodríguez, Camila Sofía; Miguel, Carolina Paula; Pozner, Roberto Gabriel; Ortiz Wilczyñski, Juan Manuel; Negrotto, Soledad; Carrera Silva, Eugenio Antonio; Heller, Paula Graciela; Schattner, Mirta Ana
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: Platelet Toll‐like receptor (TLR)2/4 are key players in amplifying the host immune response; however, their role in human megakaryo/thrombopoiesis has not yet been defined. Objectives: We evaluated whether Pam3CSK4 or lipopolysaccharide (LPS), TLR2/4 ligands respectively, modulate human megakaryocyte development and platelet production. Methods: CD34+ cells from human umbilical cord were stimulated with LPS or Pam3CSK4 with or without thrombopoietin (TPO). Results: CD34+ cells and megakaryocytes express TLR2 and TLR4 at both RNA and protein level; however, direct stimulation of CD34+ cells with LPS or Pam3CSK4 had no effect on cell growth. Interestingly, both TLR ligands markedly increased TPO‐in‐ duced CD34+ cell proliferation, megakaryocyte number and maturity, proplatelet and platelet production when added at day 0. In contrast, this synergism was not observed when TLR agonists were added 7 days after TPO addition. Interleukin‐6 (IL‐6) release was observed upon CD34+ or megakaryocyte stimulation with LPS or Pam3CSK4 but not with TPO and this effect was potentiated in combination with TPO. The increased proliferation and IL‐6 production induced by TPO + LPS or Pam3CSK4 were sup‐ pressed by TLR2/4 or IL‐6 neutralizing antibodies, as well as by PI3K/AKT and nuclear factor‐κB inhibitors. Additionally, increased proplatelet and platelet production were associated with enhanced nuclear translocation of nuclear factor‐E2. Finally, the su‐ pernatants of CD34+ cells stimulated with TPO+LPS‐induced CFU‐M colonies. Conclusions: Our data suggest that the activation of TLR2 and TLR4 in CD34+ cells and megakaryocytes in the presence of TPO may contribute to warrant platelet provi‐ sion during infection episodes by an autocrine IL‐6 loop triggered by PI3K/NF‐κB axes.
Fil: D'Atri, Lina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Rodríguez, Camila Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Miguel, Carolina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Pozner, Roberto Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Ortiz Wilczyñski, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Negrotto, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Heller, Paula Graciela. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Schattner, Mirta Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Materia
Toll-like receptors
Megakaryopoiesis
Platelets
Interleukin 6
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/106653
Acceder
id CONICETDig_bb9f15bc3039790447c9c2a334cffc8f
oai_identifier_str oai:ri.conicet.gov.ar:11336/106653
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietinD'Atri, Lina PaolaRodríguez, Camila SofíaMiguel, Carolina PaulaPozner, Roberto GabrielOrtiz Wilczyñski, Juan ManuelNegrotto, SoledadCarrera Silva, Eugenio AntonioHeller, Paula GracielaSchattner, Mirta AnaToll-like receptorsMegakaryopoiesisPlateletsInterleukin 6https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background: Platelet Toll‐like receptor (TLR)2/4 are key players in amplifying the host immune response; however, their role in human megakaryo/thrombopoiesis has not yet been defined. Objectives: We evaluated whether Pam3CSK4 or lipopolysaccharide (LPS), TLR2/4 ligands respectively, modulate human megakaryocyte development and platelet production. Methods: CD34+ cells from human umbilical cord were stimulated with LPS or Pam3CSK4 with or without thrombopoietin (TPO). Results: CD34+ cells and megakaryocytes express TLR2 and TLR4 at both RNA and protein level; however, direct stimulation of CD34+ cells with LPS or Pam3CSK4 had no effect on cell growth. Interestingly, both TLR ligands markedly increased TPO‐in‐ duced CD34+ cell proliferation, megakaryocyte number and maturity, proplatelet and platelet production when added at day 0. In contrast, this synergism was not observed when TLR agonists were added 7 days after TPO addition. Interleukin‐6 (IL‐6) release was observed upon CD34+ or megakaryocyte stimulation with LPS or Pam3CSK4 but not with TPO and this effect was potentiated in combination with TPO. The increased proliferation and IL‐6 production induced by TPO + LPS or Pam3CSK4 were sup‐ pressed by TLR2/4 or IL‐6 neutralizing antibodies, as well as by PI3K/AKT and nuclear factor‐κB inhibitors. Additionally, increased proplatelet and platelet production were associated with enhanced nuclear translocation of nuclear factor‐E2. Finally, the su‐ pernatants of CD34+ cells stimulated with TPO+LPS‐induced CFU‐M colonies. Conclusions: Our data suggest that the activation of TLR2 and TLR4 in CD34+ cells and megakaryocytes in the presence of TPO may contribute to warrant platelet provi‐ sion during infection episodes by an autocrine IL‐6 loop triggered by PI3K/NF‐κB axes.Fil: D'Atri, Lina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Rodríguez, Camila Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Miguel, Carolina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Pozner, Roberto Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Ortiz Wilczyñski, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Negrotto, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Heller, Paula Graciela. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schattner, Mirta Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaWiley Blackwell Publishing, Inc2019-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/106653D'Atri, Lina Paola; Rodríguez, Camila Sofía; Miguel, Carolina Paula; Pozner, Roberto Gabriel; Ortiz Wilczyñski, Juan Manuel; et al.; Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietin; Wiley Blackwell Publishing, Inc; Journal of Thrombosis and Haemostasis; 17; 12; 9-2019; 2196-22101538-7933CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14605info:eu-repo/semantics/altIdentifier/doi/10.1111/jth.14605info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:10:07Zoai:ri.conicet.gov.ar:11336/106653instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:10:07.946CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietin
title Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietin
spellingShingle Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietin
D'Atri, Lina Paola
Toll-like receptors
Megakaryopoiesis
Platelets
Interleukin 6
title_short Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietin
title_full Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietin
title_fullStr Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietin
title_full_unstemmed Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietin
title_sort Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietin
dc.creator.none.fl_str_mv D'Atri, Lina Paola
Rodríguez, Camila Sofía
Miguel, Carolina Paula
Pozner, Roberto Gabriel
Ortiz Wilczyñski, Juan Manuel
Negrotto, Soledad
Carrera Silva, Eugenio Antonio
Heller, Paula Graciela
Schattner, Mirta Ana
author D'Atri, Lina Paola
author_facet D'Atri, Lina Paola
Rodríguez, Camila Sofía
Miguel, Carolina Paula
Pozner, Roberto Gabriel
Ortiz Wilczyñski, Juan Manuel
Negrotto, Soledad
Carrera Silva, Eugenio Antonio
Heller, Paula Graciela
Schattner, Mirta Ana
author_role author
author2 Rodríguez, Camila Sofía
Miguel, Carolina Paula
Pozner, Roberto Gabriel
Ortiz Wilczyñski, Juan Manuel
Negrotto, Soledad
Carrera Silva, Eugenio Antonio
Heller, Paula Graciela
Schattner, Mirta Ana
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Toll-like receptors
Megakaryopoiesis
Platelets
Interleukin 6
topic Toll-like receptors
Megakaryopoiesis
Platelets
Interleukin 6
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: Platelet Toll‐like receptor (TLR)2/4 are key players in amplifying the host immune response; however, their role in human megakaryo/thrombopoiesis has not yet been defined. Objectives: We evaluated whether Pam3CSK4 or lipopolysaccharide (LPS), TLR2/4 ligands respectively, modulate human megakaryocyte development and platelet production. Methods: CD34+ cells from human umbilical cord were stimulated with LPS or Pam3CSK4 with or without thrombopoietin (TPO). Results: CD34+ cells and megakaryocytes express TLR2 and TLR4 at both RNA and protein level; however, direct stimulation of CD34+ cells with LPS or Pam3CSK4 had no effect on cell growth. Interestingly, both TLR ligands markedly increased TPO‐in‐ duced CD34+ cell proliferation, megakaryocyte number and maturity, proplatelet and platelet production when added at day 0. In contrast, this synergism was not observed when TLR agonists were added 7 days after TPO addition. Interleukin‐6 (IL‐6) release was observed upon CD34+ or megakaryocyte stimulation with LPS or Pam3CSK4 but not with TPO and this effect was potentiated in combination with TPO. The increased proliferation and IL‐6 production induced by TPO + LPS or Pam3CSK4 were sup‐ pressed by TLR2/4 or IL‐6 neutralizing antibodies, as well as by PI3K/AKT and nuclear factor‐κB inhibitors. Additionally, increased proplatelet and platelet production were associated with enhanced nuclear translocation of nuclear factor‐E2. Finally, the su‐ pernatants of CD34+ cells stimulated with TPO+LPS‐induced CFU‐M colonies. Conclusions: Our data suggest that the activation of TLR2 and TLR4 in CD34+ cells and megakaryocytes in the presence of TPO may contribute to warrant platelet provi‐ sion during infection episodes by an autocrine IL‐6 loop triggered by PI3K/NF‐κB axes.
Fil: D'Atri, Lina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Rodríguez, Camila Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Miguel, Carolina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Pozner, Roberto Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Ortiz Wilczyñski, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Negrotto, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Heller, Paula Graciela. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Schattner, Mirta Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
description Background: Platelet Toll‐like receptor (TLR)2/4 are key players in amplifying the host immune response; however, their role in human megakaryo/thrombopoiesis has not yet been defined. Objectives: We evaluated whether Pam3CSK4 or lipopolysaccharide (LPS), TLR2/4 ligands respectively, modulate human megakaryocyte development and platelet production. Methods: CD34+ cells from human umbilical cord were stimulated with LPS or Pam3CSK4 with or without thrombopoietin (TPO). Results: CD34+ cells and megakaryocytes express TLR2 and TLR4 at both RNA and protein level; however, direct stimulation of CD34+ cells with LPS or Pam3CSK4 had no effect on cell growth. Interestingly, both TLR ligands markedly increased TPO‐in‐ duced CD34+ cell proliferation, megakaryocyte number and maturity, proplatelet and platelet production when added at day 0. In contrast, this synergism was not observed when TLR agonists were added 7 days after TPO addition. Interleukin‐6 (IL‐6) release was observed upon CD34+ or megakaryocyte stimulation with LPS or Pam3CSK4 but not with TPO and this effect was potentiated in combination with TPO. The increased proliferation and IL‐6 production induced by TPO + LPS or Pam3CSK4 were sup‐ pressed by TLR2/4 or IL‐6 neutralizing antibodies, as well as by PI3K/AKT and nuclear factor‐κB inhibitors. Additionally, increased proplatelet and platelet production were associated with enhanced nuclear translocation of nuclear factor‐E2. Finally, the su‐ pernatants of CD34+ cells stimulated with TPO+LPS‐induced CFU‐M colonies. Conclusions: Our data suggest that the activation of TLR2 and TLR4 in CD34+ cells and megakaryocytes in the presence of TPO may contribute to warrant platelet provi‐ sion during infection episodes by an autocrine IL‐6 loop triggered by PI3K/NF‐κB axes.
publishDate 2019
dc.date.none.fl_str_mv 2019-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/106653
D'Atri, Lina Paola; Rodríguez, Camila Sofía; Miguel, Carolina Paula; Pozner, Roberto Gabriel; Ortiz Wilczyñski, Juan Manuel; et al.; Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietin; Wiley Blackwell Publishing, Inc; Journal of Thrombosis and Haemostasis; 17; 12; 9-2019; 2196-2210
1538-7933
CONICET Digital
CONICET
url http://hdl.handle.net/11336/106653
identifier_str_mv D'Atri, Lina Paola; Rodríguez, Camila Sofía; Miguel, Carolina Paula; Pozner, Roberto Gabriel; Ortiz Wilczyñski, Juan Manuel; et al.; Activation of toll‐like receptors 2 and 4 on CD 34 + cells increases human megakaryo/thrombopoiesis induced by thrombopoietin; Wiley Blackwell Publishing, Inc; Journal of Thrombosis and Haemostasis; 17; 12; 9-2019; 2196-2210
1538-7933
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1111/jth.14605
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
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application/pdf
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dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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