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DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis

Isaiah R Turnbull1, Jonathan E McDunn, Toshiyuki Takai

  • 1Department of Pathology and Immunology, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110.

The Journal of Experimental Medicine
|August 3, 2005
PubMed

Insights

DAP12 signaling amplifies inflammation and mortality during sepsis. Mice lacking DAP12 (DNAX-activating protein 12) showed improved survival and reduced inflammatory responses in septic shock models.

Area of Science:

  • Immunology
  • Innate Immunity
  • Inflammation

Background:

  • DAP12 (DNAX-activating protein 12) is a signaling adaptor for innate immunoreceptors.
  • Previous studies suggested both activating and inhibitory roles for DAP12 in immune responses.
  • Its in vivo role in inflammation, particularly during sepsis, remained unclear.

Purpose of the Study:

  • To investigate the in vivo role of DAP12 signaling in the context of septic shock.
  • To determine whether DAP12 signaling influences survival, cytokine production, and immune cell responses during sepsis.

Main Methods:

  • Utilized wild-type (WT) and DAP12 knockout (DAP12-/-) mouse models.
  • Induced septic shock using endotoxemia and cecal ligation and puncture (CLP) models.
  • Assessed survival rates, plasma cytokine levels, acute phase response, cellular recruitment, bacterial control, and ex vivo cytokine production.

Main Results:

  • DAP12-/- mice exhibited significantly improved survival rates in both endotoxemia and CLP-induced septic shock models compared to WT mice.
  • DAP12-/- mice displayed reduced plasma cytokine levels and a diminished acute phase response during sepsis.
  • No defects were observed in cellular recruitment or bacterial control in DAP12-/- mice.
  • Ex vivo stimulation of cells from septic mice showed that DAP12 signaling augments lipopolysaccharide-induced cytokine production.

Conclusions:

  • DAP12 signaling plays a critical role in augmenting inflammatory responses to microbial products during sepsis.
  • This augmentation of inflammation by DAP12 contributes to mortality in septic shock.
  • Targeting DAP12 signaling may offer a therapeutic strategy to mitigate sepsis-induced inflammation and improve outcomes.

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