Syndecan-1 shedding facilitates the resolution of neutrophilic inflammation by removing sequestered CXC chemokines.
Heparan sulfate binds to and regulates many inflammatory mediators in vitro, suggesting that it serves an important role in directing the progression and outcome of inflammatory responses in vivo. Here, we evaluated the role of syndecan-1, a major heparan sulfate proteoglycan, in modulating multiorgan host injury responses in murine endotoxemia. The extent of systemic inflammation was similar between endotoxemic syndecan-1-null and wild-type mice. However, high levels of CXC chemokines (KC and MIP-2), particularly at later times after LPS, were specifically sustained in multiple organs in syndecan-1-null mice and associated with exaggerated neutrophilic inflammation, organ damage, and lethality. Syndecan-1 shedding was activated in several organs of endotoxemic wild-type mice, and this associated closely with the removal of tissue-bound CXC chemokines and resolution of accumulated neutrophils. Moreover, administration of a shedding inhibitor exacerbated disease by impeding the removal of CXC chemokines and neutrophils, whereas administration of heparan sulfate inhibited the accumulation of CXC chemokines and neutrophils in tissues and attenuated multiorgan injury and lethality. These data show that syndecan-1 shedding is a critical endogenous mechanism that facilitates the resolution of neutrophilic inflammation by aiding the clearance of proinflammatory chemokines in a heparan sulfate-dependent manner.
Hayashida
Kazutaka
K
Division of Respiratory Diseases, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Parks
William C
WC
Park
Pyong Woo
PW
D000818:Animals; D054426:Chemokine CXCL2 / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism*; D019446:Endotoxemia / Q000209:etiology / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D055370:Lung Injury; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology*; D053668:Syndecan-1 / Q000502:physiology*
D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C508242:Sdc1 protein, mouse; D053668:Syndecan-1