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Sulfation of endothelial heparan sulfate mediates Staphylococcus aureus induced hepatotoxicity
Author(s) -
Golden Gregory James,
Toledo Alejandro Gómez,
Cuello Hector,
Nizet Victor,
Esko Jeffrey
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00681
Subject(s) - sepsis , heparan sulfate , immunology , glycocalyx , inflammation , organ dysfunction , intravital microscopy , staphylococcus aureus , septic shock , liver injury , medicine , endothelium , heparin , pathology , biology , microcirculation , pharmacology , bacteria , genetics
Sepsis is defined as life‐threatening organ dysfunction caused by a dysregulated host response to infection and vascular pathology. Understanding the linkage of vascular pathology to organ failure could provide a strategy for treating the disease. Heparan sulfate proteoglycans are critical components of the vascular endothelial glycocalyx and play a key role in sepsis outcome in mice. To study how heparan sulfate modulates organ‐specific vascular pathology during sepsis, we induced Staphylococcus aureus sepsis in Ndst1 f/f Tie2Cre mice, which express under‐sulfated heparan sulfate in endothelial and myeloid tissues. Hepatic coagulopathy and infarction induced by S. aureus was reduced in Ndst1 f/f Tie2Cre mice, but not in Ndst1 f/f LysMCre or Ndst1 f/f PF4Cre mice. To examine how modifying heparan sulfate structure mitigates hepatic damage, pro‐inflammatory neutrophil trafficking and behavior was monitored in the liver during sepsis. Ndst1 f/f Tie2Cre mice contained fewer extravasated neutrophils in the liver early in sepsis. Intravital microscopy in the liver further verified that Ndst1 f/f Tie2Cre mice have neutrophil trafficking deficiencies after both sterile and septic injury. Further studies will focus on the role of heparan sulfate in neutrophil trafficking and downstream neutrophil‐driven vascular dysfunction in sepsis. Support or Funding Information This work is supported by NIH P01 HL131474 and the UCSD Microbial Sciences Graduate Research Initiative Fellowship.