Endothelial Heparan Sulfate Mediates Hepatic Neutrophil Trafficking and Injury during Staphylococcus aureus Sepsis
(2021) In mBio 12(5).- Abstract
Hepatic failure is an important risk factor for poor outcome in septic patients. Using a chemical tagging workflow and high-resolution mass spectrometry, we demonstrate that rapid proteome remodeling of the vascular surfaces precedes hepatic damage in a murine model of Staphylococcus aureus sepsis. These early changes include vascular deposition of neutrophil-derived proteins, shedding of vascular receptors, and altered levels of heparin/heparan sulfate-binding factors. Modification of endothelial heparan sulfate, a major component of the vascular glycocalyx, diminishes neutrophil trafficking to the liver and reduces hepatic coagulopathy and organ damage during the systemic inflammatory response to infection. Modifying endothelial... (More)
Hepatic failure is an important risk factor for poor outcome in septic patients. Using a chemical tagging workflow and high-resolution mass spectrometry, we demonstrate that rapid proteome remodeling of the vascular surfaces precedes hepatic damage in a murine model of Staphylococcus aureus sepsis. These early changes include vascular deposition of neutrophil-derived proteins, shedding of vascular receptors, and altered levels of heparin/heparan sulfate-binding factors. Modification of endothelial heparan sulfate, a major component of the vascular glycocalyx, diminishes neutrophil trafficking to the liver and reduces hepatic coagulopathy and organ damage during the systemic inflammatory response to infection. Modifying endothelial heparan sulfate likewise reduces neutrophil trafficking in sterile hepatic injury, reflecting a more general role of heparan sulfate contribution to the modulation of leukocyte behavior during inflammation. IMPORTANCE Vascular glycocalyx remodeling is critical to sepsis pathology, but the glycocalyx components that contribute to this process remain poorly characterized. This article shows that during Staphylococcus aureus sepsis, the liver vascular glycocalyx undergoes dramatic changes in protein composition associated with neutrophilic activity and heparin/heparan sulfate binding, all before organ damage is detectable by standard circulating liver damage markers or histology. Targeted manipulation of endothelial heparan sulfate modulates S. aureus sepsis-induced hepatotoxicity by controlling the magnitude of neutrophilic infiltration into the liver in both nonsterile and sterile injury. These data identify an important vascular glycocalyx component that impacts hepatic failure during nonsterile and sterile injury.
(Less)
- author
- Golden, Gregory J
; Toledo, Alejandro Gómez
LU
; Marki, Alex
; Sorrentino, James T
; Morris, Claire
; Riley, Raquel J
; Spliid, Charlotte
; Chen, Qiongyu
; Cornax, Ingrid
; Lewis, Nathan E
; Varki, Nissi
; Malmström, Johan
LU
and Karlsson, Christofer
LU
(Less) - organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- in
- mBio
- volume
- 12
- issue
- 5
- article number
- e01181-21
- publisher
- American Society for Microbiology
- external identifiers
-
- pmid:34544271
- scopus:85121014701
- ISSN
- 2161-2129
- DOI
- 10.1128/mBio.01181-21
- language
- English
- LU publication?
- yes
- id
- d65d7d7c-dff8-4798-8c78-a0c8f05f38f9
- date added to LUP
- 2021-09-27 15:34:34
- date last changed
- 2024-06-18 06:15:50
@article{d65d7d7c-dff8-4798-8c78-a0c8f05f38f9,
abstract = {{<p>Hepatic failure is an important risk factor for poor outcome in septic patients. Using a chemical tagging workflow and high-resolution mass spectrometry, we demonstrate that rapid proteome remodeling of the vascular surfaces precedes hepatic damage in a murine model of Staphylococcus aureus sepsis. These early changes include vascular deposition of neutrophil-derived proteins, shedding of vascular receptors, and altered levels of heparin/heparan sulfate-binding factors. Modification of endothelial heparan sulfate, a major component of the vascular glycocalyx, diminishes neutrophil trafficking to the liver and reduces hepatic coagulopathy and organ damage during the systemic inflammatory response to infection. Modifying endothelial heparan sulfate likewise reduces neutrophil trafficking in sterile hepatic injury, reflecting a more general role of heparan sulfate contribution to the modulation of leukocyte behavior during inflammation. IMPORTANCE Vascular glycocalyx remodeling is critical to sepsis pathology, but the glycocalyx components that contribute to this process remain poorly characterized. This article shows that during Staphylococcus aureus sepsis, the liver vascular glycocalyx undergoes dramatic changes in protein composition associated with neutrophilic activity and heparin/heparan sulfate binding, all before organ damage is detectable by standard circulating liver damage markers or histology. Targeted manipulation of endothelial heparan sulfate modulates S. aureus sepsis-induced hepatotoxicity by controlling the magnitude of neutrophilic infiltration into the liver in both nonsterile and sterile injury. These data identify an important vascular glycocalyx component that impacts hepatic failure during nonsterile and sterile injury.</p>}},
author = {{Golden, Gregory J and Toledo, Alejandro Gómez and Marki, Alex and Sorrentino, James T and Morris, Claire and Riley, Raquel J and Spliid, Charlotte and Chen, Qiongyu and Cornax, Ingrid and Lewis, Nathan E and Varki, Nissi and Malmström, Johan and Karlsson, Christofer}},
issn = {{2161-2129}},
language = {{eng}},
number = {{5}},
publisher = {{American Society for Microbiology}},
series = {{mBio}},
title = {{Endothelial Heparan Sulfate Mediates Hepatic Neutrophil Trafficking and Injury during Staphylococcus aureus Sepsis}},
url = {{http://dx.doi.org/10.1128/mBio.01181-21}},
doi = {{10.1128/mBio.01181-21}},
volume = {{12}},
year = {{2021}},
}