title: MyD88 and Trif signaling play distinct roles in cardiac dysfunction and mortality during endotoxin shock and polymicrobial sepsis.
abstract: BACKGROUND
  Toll-like receptors (TLRs) such as TLR2, TLR4, and TLR9 contribute to the pathogenesis of polymicrobial sepsis. These TLRs signal via the common myeloid differentiation factor 88 (MyD88)-dependent pathways. TLR4 also signals through MyD88-independent but TIR domain-containing adaptor inducing interferon-β-mediated transcription factor (Trif)-dependent pathway. The role of the two signaling pathways in cardiac dysfunction during polymicrobial sepsis and endotoxin shock is unknown.
  
  
  METHODS
  Sepsis was generated by cecum ligation and puncture. Mice were divided into sham and cecum ligation and puncture groups or subjected to saline or endotoxin. Left ventricular function was assessed in a Langendorff apparatus or by echocardiography. Cytokines were examined using a multiplex immunoassay. Neutrophil migratory and phagocytic functions were assessed using flow cytometry.
  
  
  RESULTS
  In comparison with wild-type mice, MyD88(-/-) but not Trif(-/-) mice had markedly improved cardiac function and survival after cecum ligation and puncture. In comparison, both MyD88(-/-) and Trif(-/-) mice were protected from cardiac depression and mortality during endotoxin shock. Septic MyD88(-/-) but not Trif(-/-) mice had diminished cytokine production in serum and in peritoneal space in comparison with wild-type mice after cecum ligation and puncture. In contrast, both MyD88(-/-) and Trif(-/-) mice had attenuated serum cytokines in comparison with wild-type mice after endotoxin challenge. Neither MyD88(-/-) nor Trif(-/-) signaling had any effect on neutrophil phagocytic function or bacterial clearance at 24 h of polymicrobial sepsis.
  
  
  CONCLUSIONS
  These studies establish that MyD88 but not Trif signaling plays a critical role in mediating cardiac dysfunction, systemic inflammation, and mortality during polymicrobial sepsis. Both MyD88 and Trif are essential for cardiac depression and mortality during endotoxin shock.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Lin
authors.initials: L
authors.lastname: Zou
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Chan
authors.initials: C
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Chao
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000502:physiology*; D000818:Animals; D058491:Bacterial Load; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000000981:diagnostic imaging / Q000209:etiology* / Q000401:mortality; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology; D010477:Perfusion; D010538:Peritonitis / Q000382:microbiology / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D018805:Sepsis / Q000150:complications* / Q000382:microbiology / Q000401:mortality; D012772:Shock, Septic / Q000150:complications* / Q000382:microbiology / Q000401:mortality; D015398:Signal Transduction; D014463:Ultrasonography
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; C476286:Ticam1 protein, mouse