Role of the Heparan Sulfate Proteoglycan Syndecan-1 (CD138) in Delayed-Type Hypersensitivity

Abstract

The cell surface heparan sulfate proteoglycan syndecan-1 (CD138) modulates the activity of chemokines, cytokines, integrins, and other adhesion molecules which play important roles in the regulation of inflammation. We have previously shown that syndecan-1-deficient murine leukocytes display increased interactions with endothelial cells and increased diapedesis in vivo and in vitro. In this study, we demonstrate that syndecan-1 has an important function as a negative modulator in the murine contact allergy model of oxazolone-mediated delayed-type hypersensitivity (DTH). Following elicitation of the DTH response, syndecan-1-deficient mice showed an increase in leukocyte recruitment, resulting in an increased and prolonged edema formation. Expression of the cytokines TNF-␣ and IL-6 of the chemokines CCL5/RANTES and CCL-3/MIP-1␣ and of the adhesion molecule ICAM-1 were significantly increased in syndecan-1-deficient compared with wild-type mice. In wild-type mice, syndecan-1 mRNA and protein expression was reduced during the DTH response. The differentially increased adhesion of syndecan-1-deficient leukocytes to ICAM-1 was efficiently inhibited in vitro by CD18-blocking Abs, which emerges as one mechanistic explanation for the anti-inflammatory effects of syndecan-1. Collectively, our results show an important role of syndecan-1 in the contact DTH reaction, identifying syndecan-1 as a novel target in anti-inflammatory therapy.

Enoxaparin Improves the Course of Dextran Sodium Sulfate-Induced Colitis in Syndecan-1-Deficient Mice

“…Recent results suggest that Sdc1 modulates the direct interaction of ICAM-1 with its integrin counterreceptor, because CD18-blocking antibodies are able to reduce increased binding of Sdc1 KO PMN cells to ICAM-1. 12 In contrast to ICAM-1, no difference in E-selectin and P-selectin binding was observed between Sdc1 KO and wild-type neutrophils. These findings are in accordance with previous intravital microscopy data, suggesting that integrin-mediated tight leukocyte adhesion, rather than selectin-dependent leukocyte rolling, is primarily affected in Sdc1 KO mice.…”

“…19 -21 Increased recruitment of TNF-␣-producing leukocytes in Sdc1 KO mice emerges as a major mechanistic aspect of this phenotype, since Sdc1 modulates leukocyte recruitment and the inflammatory response in experimental models: in Sdc1 KO mice subjected to contact allergies, an increased expression of ICAM-1 relative to wild-type mice was found. 2,12 In addition, a differentially increased leukocyte-endothelial interaction was observed in vitro and in vivo following i.p. TNF-␣ stimulation.…”

“…Sdc1-deficient (Sdc1 KO) mice on a C57BL/6 background 5,12 and control wild-type mice were obtained from the clinical research laboratory of the Department of Gynecology, University of Muenster. Mice were bred, housed, and handled according to the guidelines of the local animal ethics committee (number A101/2005).…”

Clinical implications of leukocyte infiltration at the choroid plexus in (neuro)inflammatory disorders

“…An in vitro adhesion assay showed that the increased adhesion of Sdc1 À/À leukocytes to ICAM-1 was inhibited by a CD18-blocking antibody, which interferes with the binding of ICAM-1 to its leukocyte integrins (CD11/ CD18) [77]. Therefore, Sdc-1 and CD11/CD18 have been proposed as novel MS targets in anti-inflammatory therapy [77].…”

“…It modulates the activity of chemokines, cytokines, integrins, selectins, and other adhesion molecules, and is assumed to be a negative regulator of various inflammatory processes [76,77]. Syndecan-1 deficient (Sdc-1 À/À ) mice show exacerbated disease symptoms in several inflammatory models, such as hypersensitivity and dextran sulfate sodium (DSS)-induced colitis, in which enhanced immune cell infiltration was reported [77,78]. In Sdc-1 À/À mice, EAE is more severe and recovery is impaired [76].…”