OX40 ligand regulates inflammation and mortality in the innate immune response to sepsis

Matthew Karulf, Ann Kelly, Andrew D. Weinberg, Jeffrey (Jeff) Gold

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The initial phase of sepsis is characterized by massive inflammatory cytokine production that contributes to multisystem organ failure and death. Costimulatory molecules are a class of receptors capable of regulating cytokine production in adaptive immunity. Recent studies described their presence on neutrophils and monocytes, suggesting a potential role in the regulation of cytokine production in innate immunity. The purpose of this study was to determine the role for OX40-OX40 ligand (OX40L) interaction in the innate immune response to polymicrobial sepsis. Humans with sepsis demonstrated upregulation of OX40L on monocytes and neutrophils, with mortality and intensive care unit stay correlating with expression levels. In an animal model of polymicrobial sepsis, a direct role for OX40L in regulating inflammation was indicated by improved survival, decreased cytokine production, and a decrease in remote organ damage in OX40L-/- mice. The finding of similar results with an OX40L Ab suggests a potential therapeutic role for OX40L blockade in sepsis. The inability of anti-OX40L to provide significant protection in macrophage-depleted mice establishes macrophages as an indispensable cell type within the OX40/OX40L axis that helps to mediate the clinical signs of disease in sepsis. Conversely, the protective effect of anti-OX40L Ab in RAG1 -/- mice further confirms a T cell-independent role for OX40L stimulation in sepsis. In conclusion, our data provide an in vivo role for the OX40/OX40L system in the innate immune response during polymicrobial sepsis and suggests a potential beneficial role for therapeutic blockade of OX40L in this devastating disorder.

Original languageEnglish (US)
Pages (from-to)4856-4862
Number of pages7
JournalJournal of Immunology
Volume185
Issue number8
DOIs
StatePublished - Oct 15 2010

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OX40 Ligand
Innate Immunity
Sepsis
Inflammation
Mortality
Cytokines
Monocytes
Neutrophils
Macrophages
Adaptive Immunity

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

OX40 ligand regulates inflammation and mortality in the innate immune response to sepsis. / Karulf, Matthew; Kelly, Ann; Weinberg, Andrew D.; Gold, Jeffrey (Jeff).

In: Journal of Immunology, Vol. 185, No. 8, 15.10.2010, p. 4856-4862.

Research output: Contribution to journalArticle

Karulf, Matthew ; Kelly, Ann ; Weinberg, Andrew D. ; Gold, Jeffrey (Jeff). / OX40 ligand regulates inflammation and mortality in the innate immune response to sepsis. In: Journal of Immunology. 2010 ; Vol. 185, No. 8. pp. 4856-4862.
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abstract = "The initial phase of sepsis is characterized by massive inflammatory cytokine production that contributes to multisystem organ failure and death. Costimulatory molecules are a class of receptors capable of regulating cytokine production in adaptive immunity. Recent studies described their presence on neutrophils and monocytes, suggesting a potential role in the regulation of cytokine production in innate immunity. The purpose of this study was to determine the role for OX40-OX40 ligand (OX40L) interaction in the innate immune response to polymicrobial sepsis. Humans with sepsis demonstrated upregulation of OX40L on monocytes and neutrophils, with mortality and intensive care unit stay correlating with expression levels. In an animal model of polymicrobial sepsis, a direct role for OX40L in regulating inflammation was indicated by improved survival, decreased cytokine production, and a decrease in remote organ damage in OX40L-/- mice. The finding of similar results with an OX40L Ab suggests a potential therapeutic role for OX40L blockade in sepsis. The inability of anti-OX40L to provide significant protection in macrophage-depleted mice establishes macrophages as an indispensable cell type within the OX40/OX40L axis that helps to mediate the clinical signs of disease in sepsis. Conversely, the protective effect of anti-OX40L Ab in RAG1 -/- mice further confirms a T cell-independent role for OX40L stimulation in sepsis. In conclusion, our data provide an in vivo role for the OX40/OX40L system in the innate immune response during polymicrobial sepsis and suggests a potential beneficial role for therapeutic blockade of OX40L in this devastating disorder.",
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