Syndecan-4 Deficiency Leads to High Mortality of Lipopolysaccharide-injected Mice

Abstract

Syndecan-4 is a transmembrane heparan sulfate proteoglycan belonging to the syndecan family. Following intraperitoneal injection of lipopolysaccharide (LPS), syndecan-4-deficient mice exhibited high mortality compared with wild-type controls. Severe endotoxin shock was observed in the deficient mice: systolic blood pressure and left ventricular fractional shortening were lower in the deficient mice than in the wild-type controls 9 h after LPS injection. Although histological examinations revealed no apparent differences between two groups, the plasma level of interleukin (IL)-1␤ was higher in the deficient mice than in the wild-type controls 9 h after LPS injection. Consistent with the regulatory roles of syndecan-4, its expression in monocytes and endothelial cells of microvasculature increased in the wild-type mice after LPS administration. Although IL-1␤ was produced to the same extent by macrophages from syndecan-4-deficient and wild-type mice after LPS stimulation, inhibition of its production by transforming growth factor-␤1 was impaired in the syndecan-4-deficient macrophages. These results indicate that syndecan-4 could be involved in prevention of endotoxin shock, at least partly through the inhibitory action of transforming growth factor-␤1 on IL-1␤ production.

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

“…A role for syndecan-4 in immune responses has been indicated by previous studies revealing inflammation-related phenotypes in syndecan-4 KO mice. [171][172][173][174] Consistent with our findings in LPS-challenged hearts, syndecan-4 expression is rapidly induced in lungs by administration of LPS and Streptococcus pneumonia. 172,174 In these mouse models of bacterial pneumonia, increased levels of neutrophils and chemokines were found in the bronchoalveolar lavage (BAL) fluid of syndecan-4 KO mice.…”

“…172,174 In these mouse models of bacterial pneumonia, increased levels of neutrophils and chemokines were found in the bronchoalveolar lavage (BAL) fluid of syndecan-4 KO mice. 172,174 In studies by Nikaido et al 172 and Ishiguro et al, 171 lack of syndecan-4 was associated with increased mortality to bacterial challenge and increased levels of circulating proinflammatory cytokines, possibly due to the ability of syndecan-4 to bind and modulate the inhibitory effect of TGF-β1 on IL-1β production in macrophages. 171 We, however, found no differences in TNFα and IL-1β synthesis between WT and syndecan-4 KO hearts following LPS challenge (Paper II).…”

Critical role for syndecan-4 in dendritic cell migration during development of allergic airway inflammation

“…The target molecule should be cell specific, expressed at best only in the induction and effector phases of the allergic immune response and in a defined window 35 . Therefore, SDC4 appears not to be an optimal target since it is ubiquitously expressed 6,7 . A systemic continuous suppression of SDC4 will likely negatively affect other SDC4-mediated physiological effects with potentially severe undesired consequences.…”

“…SDCs are transmembrane heparan sulfate proteoglycans interacting with growth factors and cytokines and a variety of extracellular matrix molecules via their heparan sulfate chains 5 . While SDC4 is ubiquitously expressed at low levels, an activation-dependent upregulation of SDC4 has been reported for macrophages, DCs and CD4 þ T cells [6][7][8] . SDC4 expression is often involved in migration and adhesion of various cells including DCs [9][10][11] .…”

“…SDC4 expression is often involved in migration and adhesion of various cells including DCs [9][10][11] . Previous animal studies have shown a pivotal role for SDC4 in protecting against kidney injury 12 , limiting endotoxin shock 7 and promoting wound healing 13 . However, an inhibition of SDC4 by a specific antibody protected mice from cartilage damage in a murine model of osteoarthritis 14 .…”