Granulocyte-macrophage-colony-stimulating factor-dependent peritoneal macrophage responses determine survival in experimentally induced peritonitis and sepsis in mice

Donn Spight, Bruce Trapnell, Bin Zhao, Pierre Berclaz, Thomas P. Shanley

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a critical role in innate immunity by stimulating the differentiation of tissue macrophages via the transcription factor PU.1. Previous studies showed that GM-CSF deficient (GM-CSF-/-) mice had susceptibility to and impaired clearance of group B streptococcal bacteria by macrophages. For these studies, we hypothesized that GM-CSF-/- mice have increased susceptibility to peritonitis caused by immune dysfunction of peritoneal macrophages. We examined the role of peritoneal macrophages in pathogen clearance, cytokine responses, and survival in a murine cecal ligation and puncture (CLP) model of peritonitis/sepsis. Surprisingly, CLP minimally affected survival in GM-CSF -/- mice while markedly reducing survival in wild-type mice. This was not explained by differences in the composition of microbial flora, rates of bacterial peritonitis, or sepsis, all of which were similar in GM-CSF -/- and wild-type mice. However, survival correlated with peritoneal and serum TNF-α and IL-6 levels that were significantly lower in GM-CSF-/- than in control mice. After peritoneal LPS instillation, GM-CSF-/- mice also had improved survival and reduced TNF-α and IL-6 responses. In vitro studies demonstrated reduced secretion of TNF-α and IL-6 by peritoneal macrophages isolated from sham GM-CSF mice as compared with macrophages from sham control mice. Peritoneal instillation of GM-CSF -/- /PU.1+ macrophages, but not GM-CSF-/-/PU.1 macrophages into GM-CSF-/- mice conferred susceptibility to death after CLP or peritoneal LPS exposure. These results demonstrate that GM-CSF -/PU.1-dependent peritoneal macrophage responses are a critical determinant of survival after experimentally induced peritonitis/sepsis or exposure to LPS and have implications for therapies to treat such infections.

Original languageEnglish (US)
Pages (from-to)434-442
Number of pages9
JournalShock
Volume30
Issue number4
DOIs
StatePublished - Oct 2008
Externally publishedYes

Fingerprint

Peritoneal Macrophages
Granulocyte-Macrophage Colony-Stimulating Factor
Peritonitis
Sepsis
Macrophages
Punctures
Ligation
Interleukin-6
Innate Immunity

Keywords

  • Cecal ligation and puncture
  • Granulocyte-macrophage-colony- stimulating factor
  • Macrophage
  • Sepsis

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Emergency Medicine

Cite this

Granulocyte-macrophage-colony-stimulating factor-dependent peritoneal macrophage responses determine survival in experimentally induced peritonitis and sepsis in mice. / Spight, Donn; Trapnell, Bruce; Zhao, Bin; Berclaz, Pierre; Shanley, Thomas P.

In: Shock, Vol. 30, No. 4, 10.2008, p. 434-442.

Research output: Contribution to journalArticle

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abstract = "Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a critical role in innate immunity by stimulating the differentiation of tissue macrophages via the transcription factor PU.1. Previous studies showed that GM-CSF deficient (GM-CSF-/-) mice had susceptibility to and impaired clearance of group B streptococcal bacteria by macrophages. For these studies, we hypothesized that GM-CSF-/- mice have increased susceptibility to peritonitis caused by immune dysfunction of peritoneal macrophages. We examined the role of peritoneal macrophages in pathogen clearance, cytokine responses, and survival in a murine cecal ligation and puncture (CLP) model of peritonitis/sepsis. Surprisingly, CLP minimally affected survival in GM-CSF -/- mice while markedly reducing survival in wild-type mice. This was not explained by differences in the composition of microbial flora, rates of bacterial peritonitis, or sepsis, all of which were similar in GM-CSF -/- and wild-type mice. However, survival correlated with peritoneal and serum TNF-α and IL-6 levels that were significantly lower in GM-CSF-/- than in control mice. After peritoneal LPS instillation, GM-CSF-/- mice also had improved survival and reduced TNF-α and IL-6 responses. In vitro studies demonstrated reduced secretion of TNF-α and IL-6 by peritoneal macrophages isolated from sham GM-CSF mice as compared with macrophages from sham control mice. Peritoneal instillation of GM-CSF -/- /PU.1+ macrophages, but not GM-CSF-/-/PU.1 macrophages into GM-CSF-/- mice conferred susceptibility to death after CLP or peritoneal LPS exposure. These results demonstrate that GM-CSF -/PU.1-dependent peritoneal macrophage responses are a critical determinant of survival after experimentally induced peritonitis/sepsis or exposure to LPS and have implications for therapies to treat such infections.",
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