Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patien...

Autores: de Luca, Geraldine; Goette, Nora Paula; Lev, Paola Roxana; Baroni Pietto, Maria Constanza; Marin Oyarzún, Cecilia Paola; Castro Ríos, Miguel A.; Moiraghi, Beatriz; Sackmann, Federico; Kamiya, Laureano Julian; Verri, Veronica; Caula, Victoria; Fernandez, Vanina; Vicente, Angeles; Pose Cabarcos, Julio; Caruso, Vanesa; Camacho Rodríguez, Maria Fernanda; Larripa, Irene Beatriz; Khoury, Marina; Marta, Rosana Fernanda; Glembotsky, Ana Claudia; Heller, Paula Graciela
Año de publicación: 2024
Idioma: inglés
Tipo de recurso: artículo
Estado: versión publicada
Descripción: Inflammation plays a pivotal role in the pathogenesis of primary and post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) in close cooperation with the underlying molecular drivers. This inflammatory state is induced by a dynamic spectrum of inflammatory cytokines, although recent evidence points to the participation of additional soluble inflammatory mediators. Damage-associated molecular patterns (DAMPs) represent endogenous signals released upon cell death or damage which trigger a potent innate immune response. We assessed the contribution of two prototypical DAMPs, HMGB1 and S100A8/A9, to MF inflammation. Circulating HMGB1 and S100A8/A9 were elevated in MF patients in parallel to the degree of systemic inflammation and levels increased progressively during advanced disease stages. Patients with elevated DAMPs had higher frequency of adverse clinical features, such as anemia, and inferior survival, suggesting their contribution to disease progression. Monocytes, which are key players in MF inflammation, were identified as a source of S100A8/A9 but not HMGB1 release, while both DAMPs correlated with cell death parameters, such as serum LDH and cell-free DNA, indicating that passive release is an additional mechanism leading to increased DAMPs. HMGB1 and S100A8/A9 promote inflammation through binding to Toll-like receptor (TLR) 4, whereas the former also binds TLR2. Monocytes from MF patients were shown to be hyperactivated at baseline, as reflected by higher CD11b and tissue factor exposure and increased expression levels of proinflammatory cytokines IL-1β and IL-6. Patient monocytes showed preserved TLR4 and TLR2 expression and were able to mount normal or even exacerbated functional responses and cytokine upregulation following stimulation of TLR4 and TLR2. Elevated levels of endogenous TLR ligands HMGB1 and S100A8/A9 coupled to the finding of preserved or hyperreactive TLR-triggered responses indicate that DAMPs may promote monocyte activation and cytokine production in MF, fueling inflammation. Plasma IL-1β and IL-6 were elevated in MF and correlated with DAMPs levels, raising the possibility that DAMPs could contribute to cytokine generation in vivo. In conclusion, this study highlights that, in cooperation with classic proinflammatory cytokines, DAMPs represent additional inflammatory mediators that may participate in the generation of MF inflammatory state, potentially providing novel biomarkers of disease progression and new therapeutic targets.
Fil: de Luca, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Goette, Nora Paula. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Lev, Paola Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Baroni Pietto, Maria Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Marin Oyarzún, Cecilia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Castro Ríos, Miguel A.. Consultorios Hematologicos; Argentina
Fil: Moiraghi, Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina
Fil: Sackmann, Federico. Centro de Hematologia Pavlovsky; Argentina. Fundación Para Combatir la Leucemia; Argentina
Fil: Kamiya, Laureano Julian. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Verri, Veronica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Caula, Victoria. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Fernandez, Vanina. Hospital Nacional Profesor Alejandro Posadas; Argentina
Fil: Vicente, Angeles. Hospital Alemán; Argentina
Fil: Pose Cabarcos, Julio. Sanatorio "Otamendi y Miroli S. A."; Argentina
Fil: Caruso, Vanesa. Departamento de Hematología; Argentina
Fil: Camacho Rodríguez, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Khoury, Marina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Materia: HMGB1
S100A8/A9
Toll-like receptors
monocyte
Nivel de accesibilidad: acceso abierto
Condiciones de uso: https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
Institución: Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador: oai:ri.conicet.gov.ar:11336/266788

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network_acronym_str	CONICETDig
repository_id_str	3498
network_name_str	CONICET Digital (CONICET)
spelling	Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosisde Luca, GeraldineGoette, Nora PaulaLev, Paola RoxanaBaroni Pietto, Maria ConstanzaMarin Oyarzún, Cecilia PaolaCastro Ríos, Miguel A.Moiraghi, BeatrizSackmann, FedericoKamiya, Laureano JulianVerri, VeronicaCaula, VictoriaFernandez, VaninaVicente, AngelesPose Cabarcos, JulioCaruso, VanesaCamacho Rodríguez, Maria FernandaLarripa, Irene BeatrizKhoury, MarinaMarta, Rosana FernandaGlembotsky, Ana ClaudiaHeller, Paula GracielaHMGB1S100A8/A9Toll-like receptorsmonocytehttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Inflammation plays a pivotal role in the pathogenesis of primary and post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) in close cooperation with the underlying molecular drivers. This inflammatory state is induced by a dynamic spectrum of inflammatory cytokines, although recent evidence points to the participation of additional soluble inflammatory mediators. Damage-associated molecular patterns (DAMPs) represent endogenous signals released upon cell death or damage which trigger a potent innate immune response. We assessed the contribution of two prototypical DAMPs, HMGB1 and S100A8/A9, to MF inflammation. Circulating HMGB1 and S100A8/A9 were elevated in MF patients in parallel to the degree of systemic inflammation and levels increased progressively during advanced disease stages. Patients with elevated DAMPs had higher frequency of adverse clinical features, such as anemia, and inferior survival, suggesting their contribution to disease progression. Monocytes, which are key players in MF inflammation, were identified as a source of S100A8/A9 but not HMGB1 release, while both DAMPs correlated with cell death parameters, such as serum LDH and cell-free DNA, indicating that passive release is an additional mechanism leading to increased DAMPs. HMGB1 and S100A8/A9 promote inflammation through binding to Toll-like receptor (TLR) 4, whereas the former also binds TLR2. Monocytes from MF patients were shown to be hyperactivated at baseline, as reflected by higher CD11b and tissue factor exposure and increased expression levels of proinflammatory cytokines IL-1β and IL-6. Patient monocytes showed preserved TLR4 and TLR2 expression and were able to mount normal or even exacerbated functional responses and cytokine upregulation following stimulation of TLR4 and TLR2. Elevated levels of endogenous TLR ligands HMGB1 and S100A8/A9 coupled to the finding of preserved or hyperreactive TLR-triggered responses indicate that DAMPs may promote monocyte activation and cytokine production in MF, fueling inflammation. Plasma IL-1β and IL-6 were elevated in MF and correlated with DAMPs levels, raising the possibility that DAMPs could contribute to cytokine generation in vivo. In conclusion, this study highlights that, in cooperation with classic proinflammatory cytokines, DAMPs represent additional inflammatory mediators that may participate in the generation of MF inflammatory state, potentially providing novel biomarkers of disease progression and new therapeutic targets.Fil: de Luca, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Goette, Nora Paula. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lev, Paola Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Baroni Pietto, Maria Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Marin Oyarzún, Cecilia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Castro Ríos, Miguel A.. Consultorios Hematologicos; ArgentinaFil: Moiraghi, Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Sackmann, Federico. Centro de Hematologia Pavlovsky; Argentina. Fundación Para Combatir la Leucemia; ArgentinaFil: Kamiya, Laureano Julian. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Verri, Veronica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Caula, Victoria. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Fernandez, Vanina. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Vicente, Angeles. Hospital Alemán; ArgentinaFil: Pose Cabarcos, Julio. Sanatorio "Otamendi y Miroli S. A."; ArgentinaFil: Caruso, Vanesa. Departamento de Hematología; ArgentinaFil: Camacho Rodríguez, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Khoury, Marina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFrontiers Media2024-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/266788de Luca, Geraldine; Goette, Nora Paula; Lev, Paola Roxana; Baroni Pietto, Maria Constanza; Marin Oyarzún, Cecilia Paola; et al.; Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis; Frontiers Media; Frontiers in Immunology; 15; 9-2024; 1-171664-3224CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fimmu.2024.1365015/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2024.1365015info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-12T09:56:50Zoai:ri.conicet.gov.ar:11336/266788instacron: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:34982025-11-12 09:56:50.294CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv	Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis
title	Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis
spellingShingle	Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis de Luca, Geraldine HMGB1 S100A8/A9 Toll-like receptors monocyte
title_short	Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis
title_full	Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis
title_fullStr	Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis
title_full_unstemmed	Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis
title_sort	Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis
dc.creator.none.fl_str_mv	de Luca, Geraldine Goette, Nora Paula Lev, Paola Roxana Baroni Pietto, Maria Constanza Marin Oyarzún, Cecilia Paola Castro Ríos, Miguel A. Moiraghi, Beatriz Sackmann, Federico Kamiya, Laureano Julian Verri, Veronica Caula, Victoria Fernandez, Vanina Vicente, Angeles Pose Cabarcos, Julio Caruso, Vanesa Camacho Rodríguez, Maria Fernanda Larripa, Irene Beatriz Khoury, Marina Marta, Rosana Fernanda Glembotsky, Ana Claudia Heller, Paula Graciela
author	de Luca, Geraldine
author_facet	de Luca, Geraldine Goette, Nora Paula Lev, Paola Roxana Baroni Pietto, Maria Constanza Marin Oyarzún, Cecilia Paola Castro Ríos, Miguel A. Moiraghi, Beatriz Sackmann, Federico Kamiya, Laureano Julian Verri, Veronica Caula, Victoria Fernandez, Vanina Vicente, Angeles Pose Cabarcos, Julio Caruso, Vanesa Camacho Rodríguez, Maria Fernanda Larripa, Irene Beatriz Khoury, Marina Marta, Rosana Fernanda Glembotsky, Ana Claudia Heller, Paula Graciela
author_role	author
author2	Goette, Nora Paula Lev, Paola Roxana Baroni Pietto, Maria Constanza Marin Oyarzún, Cecilia Paola Castro Ríos, Miguel A. Moiraghi, Beatriz Sackmann, Federico Kamiya, Laureano Julian Verri, Veronica Caula, Victoria Fernandez, Vanina Vicente, Angeles Pose Cabarcos, Julio Caruso, Vanesa Camacho Rodríguez, Maria Fernanda Larripa, Irene Beatriz Khoury, Marina Marta, Rosana Fernanda Glembotsky, Ana Claudia Heller, Paula Graciela
author2_role	author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	HMGB1 S100A8/A9 Toll-like receptors monocyte
topic	HMGB1 S100A8/A9 Toll-like receptors monocyte
purl_subject.fl_str_mv	https://purl.org/becyt/ford/3.3 https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv	Inflammation plays a pivotal role in the pathogenesis of primary and post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) in close cooperation with the underlying molecular drivers. This inflammatory state is induced by a dynamic spectrum of inflammatory cytokines, although recent evidence points to the participation of additional soluble inflammatory mediators. Damage-associated molecular patterns (DAMPs) represent endogenous signals released upon cell death or damage which trigger a potent innate immune response. We assessed the contribution of two prototypical DAMPs, HMGB1 and S100A8/A9, to MF inflammation. Circulating HMGB1 and S100A8/A9 were elevated in MF patients in parallel to the degree of systemic inflammation and levels increased progressively during advanced disease stages. Patients with elevated DAMPs had higher frequency of adverse clinical features, such as anemia, and inferior survival, suggesting their contribution to disease progression. Monocytes, which are key players in MF inflammation, were identified as a source of S100A8/A9 but not HMGB1 release, while both DAMPs correlated with cell death parameters, such as serum LDH and cell-free DNA, indicating that passive release is an additional mechanism leading to increased DAMPs. HMGB1 and S100A8/A9 promote inflammation through binding to Toll-like receptor (TLR) 4, whereas the former also binds TLR2. Monocytes from MF patients were shown to be hyperactivated at baseline, as reflected by higher CD11b and tissue factor exposure and increased expression levels of proinflammatory cytokines IL-1β and IL-6. Patient monocytes showed preserved TLR4 and TLR2 expression and were able to mount normal or even exacerbated functional responses and cytokine upregulation following stimulation of TLR4 and TLR2. Elevated levels of endogenous TLR ligands HMGB1 and S100A8/A9 coupled to the finding of preserved or hyperreactive TLR-triggered responses indicate that DAMPs may promote monocyte activation and cytokine production in MF, fueling inflammation. Plasma IL-1β and IL-6 were elevated in MF and correlated with DAMPs levels, raising the possibility that DAMPs could contribute to cytokine generation in vivo. In conclusion, this study highlights that, in cooperation with classic proinflammatory cytokines, DAMPs represent additional inflammatory mediators that may participate in the generation of MF inflammatory state, potentially providing novel biomarkers of disease progression and new therapeutic targets. Fil: de Luca, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Goette, Nora Paula. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Lev, Paola Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Baroni Pietto, Maria Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Marin Oyarzún, Cecilia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Castro Ríos, Miguel A.. Consultorios Hematologicos; Argentina Fil: Moiraghi, Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina Fil: Sackmann, Federico. Centro de Hematologia Pavlovsky; Argentina. Fundación Para Combatir la Leucemia; Argentina Fil: Kamiya, Laureano Julian. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Verri, Veronica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Caula, Victoria. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Fernandez, Vanina. Hospital Nacional Profesor Alejandro Posadas; Argentina Fil: Vicente, Angeles. Hospital Alemán; Argentina Fil: Pose Cabarcos, Julio. Sanatorio "Otamendi y Miroli S. A."; Argentina Fil: Caruso, Vanesa. Departamento de Hematología; Argentina Fil: Camacho Rodríguez, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Khoury, Marina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
description	Inflammation plays a pivotal role in the pathogenesis of primary and post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) in close cooperation with the underlying molecular drivers. This inflammatory state is induced by a dynamic spectrum of inflammatory cytokines, although recent evidence points to the participation of additional soluble inflammatory mediators. Damage-associated molecular patterns (DAMPs) represent endogenous signals released upon cell death or damage which trigger a potent innate immune response. We assessed the contribution of two prototypical DAMPs, HMGB1 and S100A8/A9, to MF inflammation. Circulating HMGB1 and S100A8/A9 were elevated in MF patients in parallel to the degree of systemic inflammation and levels increased progressively during advanced disease stages. Patients with elevated DAMPs had higher frequency of adverse clinical features, such as anemia, and inferior survival, suggesting their contribution to disease progression. Monocytes, which are key players in MF inflammation, were identified as a source of S100A8/A9 but not HMGB1 release, while both DAMPs correlated with cell death parameters, such as serum LDH and cell-free DNA, indicating that passive release is an additional mechanism leading to increased DAMPs. HMGB1 and S100A8/A9 promote inflammation through binding to Toll-like receptor (TLR) 4, whereas the former also binds TLR2. Monocytes from MF patients were shown to be hyperactivated at baseline, as reflected by higher CD11b and tissue factor exposure and increased expression levels of proinflammatory cytokines IL-1β and IL-6. Patient monocytes showed preserved TLR4 and TLR2 expression and were able to mount normal or even exacerbated functional responses and cytokine upregulation following stimulation of TLR4 and TLR2. Elevated levels of endogenous TLR ligands HMGB1 and S100A8/A9 coupled to the finding of preserved or hyperreactive TLR-triggered responses indicate that DAMPs may promote monocyte activation and cytokine production in MF, fueling inflammation. Plasma IL-1β and IL-6 were elevated in MF and correlated with DAMPs levels, raising the possibility that DAMPs could contribute to cytokine generation in vivo. In conclusion, this study highlights that, in cooperation with classic proinflammatory cytokines, DAMPs represent additional inflammatory mediators that may participate in the generation of MF inflammatory state, potentially providing novel biomarkers of disease progression and new therapeutic targets.
publishDate	2024
dc.date.none.fl_str_mv	2024-09
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/11336/266788 de Luca, Geraldine; Goette, Nora Paula; Lev, Paola Roxana; Baroni Pietto, Maria Constanza; Marin Oyarzún, Cecilia Paola; et al.; Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis; Frontiers Media; Frontiers in Immunology; 15; 9-2024; 1-17 1664-3224 CONICET Digital CONICET
url	http://hdl.handle.net/11336/266788
identifier_str_mv	de Luca, Geraldine; Goette, Nora Paula; Lev, Paola Roxana; Baroni Pietto, Maria Constanza; Marin Oyarzún, Cecilia Paola; et al.; Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis; Frontiers Media; Frontiers in Immunology; 15; 9-2024; 1-17 1664-3224 CONICET Digital CONICET
dc.language.none.fl_str_mv	eng
language	eng
dc.relation.none.fl_str_mv	info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fimmu.2024.1365015/full info:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2024.1365015
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv	openAccess
rights_invalid_str_mv	https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv	application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf
dc.publisher.none.fl_str_mv	Frontiers Media
publisher.none.fl_str_mv	Frontiers Media
dc.source.none.fl_str_mv	reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas
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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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score	13.24909

Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patien...

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