Granulocyte-macrophage-colony-stimulating factor-dependent peritoneal macrophage responses determine survival in experimentally induced peritonitis and sepsis in mice.
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 GMCSF-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-alpha 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-alpha and IL-6 responses. In vitro studies demonstrated reduced secretion of TNF-alpha 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-CSFY/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.
Spight
Donn
D
Department of Surgery, University of Cincinnati, Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
Trapnell
Bruce
B
Zhao
Bin
B
Berclaz
Pierre
P
Shanley
Thomas P
TP
D000818:Animals; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D007107:Immune System; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010538:Peritonitis / Q000097:blood* / Q000378:metabolism; D018805:Sepsis / Q000097:blood* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor