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Cutting edge: myeloid differentiation factor 88 deficiency improves resistance against sepsis caused by polymicrobial
Heike Weighardt1, Simone Kaiser-Moore, Ramunas M Vabulas
1Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Abstract:
Toll-like receptors (TLRs) are important for the activation of innate immune cells upon encounter of microbial pathogens. The present study investigated the potential roles of TLR2, TLR4, and the signaling protein myeloid differentiation factor 88 (MyD88) in polymicrobial septic peritonitis. Whereas both TLR2 and TLR4 were dispensable for host defense against septic peritonitis, MyD88-deficient mice were protected in this infection model. Recruitment of neutrophils to the septic focus and bacterial clearance were normal in MyD88-deficient mice. In contrast, the systemic inflammatory response was strongly attenuated in the absence of MyD88. Surprisingly, MyD88 deficiency did not alter cytokine and chemokine production in spleen, but markedly reduced the inflammatory response in liver and lung. Production of monocyte chemoattractant protein-1 and macrophage-inflammatory protein-1alpha was entirely independent of MyD88. These results imply a central role of MyD88 for the systemic immune pathology of polymicrobial sepsis and show that cytokine production in spleen and induction of certain chemokines are MyD88 independent.
Insights
Myeloid differentiation factor 88 (MyD88) plays a key role in the systemic immune response to polymicrobial sepsis. While Toll-like receptors 2 and 4 are not essential, MyD88 deficiency protects mice by reducing systemic inflammation.
Area of Science:
- Immunology
- Infectious Disease
Background:
- Toll-like receptors (TLRs) are crucial for innate immunity against microbial pathogens.
- Polymicrobial septic peritonitis serves as a model to study systemic infection responses.
Purpose of the Study:
- To investigate the roles of TLR2, TLR4, and MyD88 in polymicrobial septic peritonitis.
- To understand MyD88's specific contribution to the systemic inflammatory pathology.
Main Methods:
- Utilized MyD88-deficient mice and wild-type controls in a polymicrobial septic peritonitis model.
- Assessed neutrophil recruitment, bacterial clearance, and systemic inflammatory markers in different organs.
Main Results:
- TLR2 and TLR4 were dispensable for host defense in this sepsis model.
- MyD88-deficient mice showed protection, with normal neutrophil recruitment and bacterial clearance.
- Systemic inflammation was significantly attenuated in MyD88-deficient mice, particularly in the liver and lung.
- Certain chemokine productions (MCP-1, MIP-1alpha) were MyD88-independent.
Conclusions:
- MyD88 is central to the systemic immune pathology of polymicrobial sepsis.
- Spleen cytokine production and some chemokine inductions are independent of MyD88 signaling.