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MyD88 and Trif signaling play distinct roles in cardiac dysfunction and mortality during endotoxin shock and

Yan Feng1, Lin Zou, Ming Zhang

  • 1Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Anesthesiology
|July 28, 2011
PubMed
Abstract

Insights

MyD88 signaling critically mediates cardiac dysfunction and mortality in polymicrobial sepsis, while both MyD88 and Trif pathways are vital in endotoxin shock.

Area of Science:

  • Immunology
  • Cardiovascular Biology
  • Sepsis Pathogenesis

Background:

  • Toll-like receptors (TLRs) mediate sepsis pathogenesis via MyD88-dependent and MyD88-independent pathways.
  • MyD88 signaling is crucial for TLR2, TLR4, and TLR9 activation.
  • Trif-dependent pathways are involved in TLR4 signaling, but their role in sepsis-induced cardiac dysfunction is unclear.

Purpose of the Study:

  • To investigate the roles of MyD88 and Trif signaling pathways in cardiac dysfunction during polymicrobial sepsis and endotoxin shock.
  • To elucidate the contribution of these pathways to systemic inflammation and mortality.

Main Methods:

  • Polymicrobial sepsis was induced via cecum ligation and puncture in mice.
  • Endotoxin shock was induced using lipopolysaccharide.
  • Cardiac function was assessed using Langendorff apparatus and echocardiography.
  • Serum and peritoneal cytokines were quantified using multiplex immunoassay.
  • Neutrophil function and bacterial clearance were evaluated by flow cytometry.

Main Results:

  • MyD88(-/-) mice exhibited improved cardiac function and survival in polymicrobial sepsis compared to wild-type.
  • Trif(-/-) mice showed no significant protection in polymicrobial sepsis.
  • Both MyD88(-/-) and Trif(-/-) mice were protected from cardiac depression and mortality during endotoxin shock.
  • MyD88(-/-) mice had reduced cytokine production in polymicrobial sepsis, while both MyD88(-/-) and Trif(-/-) mice had attenuated cytokines in endotoxin shock.
  • Neither pathway affected neutrophil function or bacterial clearance at 24 hours in sepsis.

Conclusions:

  • MyD88 signaling is essential for cardiac dysfunction, inflammation, and mortality in polymicrobial sepsis.
  • Both MyD88 and Trif signaling pathways are critical for cardiac depression and mortality in endotoxin shock.
  • These findings highlight distinct roles for MyD88 and Trif in sepsis and endotoxin-induced cardiac injury.

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