Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes

Abstract Sepsis remains a significant health burden and a major clinical need exists for therapeutics to dampen the excessive and uncontrolled immune activation. Nuclear protein high mobility group box protein 1 (HMGB1) is released following cell death and is a late mediator in sepsis pathogenesis....

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Autores principales:	Natalie E. Stevens, Marianne J. Chapman, Cara K. Fraser, Tim R. Kuchel, John D. Hayball, Kerrilyn R. Diener
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/db850342f341408eaced7e104b682ab6
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spelling	oai:doaj.org-article:db850342f341408eaced7e104b682ab62021-12-02T12:30:27ZTherapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes10.1038/s41598-017-06205-z2045-2322https://doaj.org/article/db850342f341408eaced7e104b682ab62017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06205-zhttps://doaj.org/toc/2045-2322Abstract Sepsis remains a significant health burden and a major clinical need exists for therapeutics to dampen the excessive and uncontrolled immune activation. Nuclear protein high mobility group box protein 1 (HMGB1) is released following cell death and is a late mediator in sepsis pathogenesis. While approaches targeting HMGB1 have demonstrated reduced mortality in pre-clinical models of sepsis, the impact of HMGB1 blockade on the complex septic inflammatory milieu and the development of subsequent immunosuppression remain enigmatic. Analysis of plasma samples obtained from septic shock patients established an association between increased HMGB1 and non-survival, higher APACHE II scores, and increased pro-inflammatory cytokine responses. Pre-clinically, administration of neutralising ovine anti-HMGB1 polyclonal antibodies improved survival in murine endotoxaemia and caecal ligation and puncture-induced sepsis models, and altered early cytokine profiles to one which corresponded to patterns observed in the surviving patient cohort. Additionally, anti-HMGB1 treated murine sepsis survivors were significantly more resistant to secondary bacterial infection and exhibited altered innate immune cell phenotypes and cytokine responses. These findings demonstrate that anti-HMGB1 antibodies alter inflammation in murine sepsis models and reduce sepsis mortality without potentiating immunosuppression.Natalie E. StevensMarianne J. ChapmanCara K. FraserTim R. KuchelJohn D. HayballKerrilyn R. DienerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Natalie E. Stevens Marianne J. Chapman Cara K. Fraser Tim R. Kuchel John D. Hayball Kerrilyn R. Diener Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes
description	Abstract Sepsis remains a significant health burden and a major clinical need exists for therapeutics to dampen the excessive and uncontrolled immune activation. Nuclear protein high mobility group box protein 1 (HMGB1) is released following cell death and is a late mediator in sepsis pathogenesis. While approaches targeting HMGB1 have demonstrated reduced mortality in pre-clinical models of sepsis, the impact of HMGB1 blockade on the complex septic inflammatory milieu and the development of subsequent immunosuppression remain enigmatic. Analysis of plasma samples obtained from septic shock patients established an association between increased HMGB1 and non-survival, higher APACHE II scores, and increased pro-inflammatory cytokine responses. Pre-clinically, administration of neutralising ovine anti-HMGB1 polyclonal antibodies improved survival in murine endotoxaemia and caecal ligation and puncture-induced sepsis models, and altered early cytokine profiles to one which corresponded to patterns observed in the surviving patient cohort. Additionally, anti-HMGB1 treated murine sepsis survivors were significantly more resistant to secondary bacterial infection and exhibited altered innate immune cell phenotypes and cytokine responses. These findings demonstrate that anti-HMGB1 antibodies alter inflammation in murine sepsis models and reduce sepsis mortality without potentiating immunosuppression.
format	article
author	Natalie E. Stevens Marianne J. Chapman Cara K. Fraser Tim R. Kuchel John D. Hayball Kerrilyn R. Diener
author_facet	Natalie E. Stevens Marianne J. Chapman Cara K. Fraser Tim R. Kuchel John D. Hayball Kerrilyn R. Diener
author_sort	Natalie E. Stevens
title	Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes
title_short	Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes
title_full	Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes
title_fullStr	Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes
title_full_unstemmed	Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes
title_sort	therapeutic targeting of hmgb1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/db850342f341408eaced7e104b682ab6
work_keys_str_mv	AT natalieestevens therapeutictargetingofhmgb1duringexperimentalsepsismodulatestheinflammatorycytokineprofiletooneassociatedwithimprovedclinicaloutcomes AT mariannejchapman therapeutictargetingofhmgb1duringexperimentalsepsismodulatestheinflammatorycytokineprofiletooneassociatedwithimprovedclinicaloutcomes AT carakfraser therapeutictargetingofhmgb1duringexperimentalsepsismodulatestheinflammatorycytokineprofiletooneassociatedwithimprovedclinicaloutcomes AT timrkuchel therapeutictargetingofhmgb1duringexperimentalsepsismodulatestheinflammatorycytokineprofiletooneassociatedwithimprovedclinicaloutcomes AT johndhayball therapeutictargetingofhmgb1duringexperimentalsepsismodulatestheinflammatorycytokineprofiletooneassociatedwithimprovedclinicaloutcomes AT kerrilynrdiener therapeutictargetingofhmgb1duringexperimentalsepsismodulatestheinflammatorycytokineprofiletooneassociatedwithimprovedclinicaloutcomes
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Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes

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