Syndecan-1 shedding facilitates the resolution of neutrophilic inflammation by removing sequestered CXC chemokines

Abstract

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. (Blood. 2009;114:3033-3043)

Shedding of Syndecan-1/CXCL1 Complexes by Matrix Metalloproteinase 7 Functions as an Epithelial Checkpoint of Neutrophil Activation

“…Combined with findings we reported previously (9,10,26,27), we propose that cell-bound syndecan-1 with CXCL1 bound to its GAG chains functions as a checkpoint to prevent premature neutrophil activation. If still intact on the cell surface, syndecan-1/ CXCL1 complexes would support neutrophil binding, yet are not sufficient to facilitate neutrophil activation ( Figure 6).…”

Syndecan-1, a Cell Surface Proteoglycan, Negatively Regulates Initial Leukocyte Recruitment to the Brain across the Choroid Plexus in Murine Experimental Autoimmune Encephalomyelitis

“…Although syndecan-1 knockout (Sdc-1 2/2 ) mice show exacerbated disease symptoms in several inflammatory models (14), precisely why this is the case remains unclear. Most studies report enhanced immune cell infiltration in Sdc-1 2/2 mice, which has been correlated with enhanced extravasation from postcapillary venules because of effects ranging from modulation of integrin activity and interaction with cell adhesion molecules (14,15) to modulation of cytokine and chemokine gradients (16). Yet, the expression of syndecan-1 on endothelium and immune cells in vivo is difficult to detect, with the notable exception of B lymphocytes, which may be partially because of its dynamic regulation (9,(17)(18)(19).…”

Shedding; towards a new paradigm of syndecan function in cancer

“…Syndecan-1 shedding facilitates the resolution of neutrophilic inflammation by removing sequestered CXC chemokines. Consistent with this, treatment with a shedding inhibitor prevents the clearance of CXC chemokines and exacerbates disease (54). Therefore, shed syndecans may promote cancer by sequestrating inhibitory signals.…”