Abstract
Oversulfated chondroitin sulfate (OSCS), a member of the glycosaminoglycan (GAG) family, was a contaminant in heparin that was linked to the 2008 heparin adverse events in the US. Because of its highly negative charge, OSCS can interact with many components of the contact and immune systems. We have previously demonstrated that OSCS inhibited the complement classical pathway by binding C1 inhibitor and potentiating its interaction with C1s. In the present study, by using surface plasmon resonance, we found OSCS interacts with T cell chemokines that can impact adaptive immunity. The binding of OSCS to stromal cell-derived factor-1 (SDF-1) chemokines, SDF-1α and SDF-1β, caused a significant change in the secondary structures of these chemokines as detected by far-ultraviolet circular dichroism spectra analysis. Functionally, OSCS binding profoundly inhibited SDF-1-induced calcium mobilization and T cell chemotaxis. Imaging flow cytometry revealed T cell morphological changes mediated by SDF-1α were completely blocked by OSCS. We conclude that the OSCS, a past contaminant in heparin, has broad interactions with the components of the human immune system beyond the contact and complement systems, and that may explain, in part, prior OSCS-related adverse events, while suggesting potentially useful therapeutic applications for related GAGs in the control of inflammation.
Highlights
Oversulfated chondroitin sulfate (OSCS), a contaminant in heparin linked to the 2008 heparin adverse events in the United States, has become the subject of multidisciplinary investigations [1,2]
OSCS Binds to Chemokines In order to test if OSCS interacts with chemokines, a group of human CC, CXC and XC chemokines, many of which target T cells, were tested for their binding to OSCS using surface plasmon resonance (Biacore)
In the present report, using surface plasmon resonance, we show that OSCS has strong binding with chemokines and may influence the regulation of the immune system through modulating chemokine-driven functions, such as immune cell migration
Summary
Oversulfated chondroitin sulfate (OSCS), a contaminant in heparin linked to the 2008 heparin adverse events in the United States, has become the subject of multidisciplinary investigations [1,2]. OSCS was found to cause the activation of contact system ( known as the intrinsic pathway of coagulation or kallikrein/kinin system [3]) through binding with factor XII and generation of plasma kallikrein and bradykinin, as well as the anaphylatoxins C3a and C5a [4,5]. OSCS interacts with other parts of the innate immune system including most of the elements in the classical complement pathway [6]. Surface plasmon resonance assays showed OSCS has stronger binding than chondroitin sulfate A (CSA), its less sulfated progenitor, and heparin to a variety of plasma proteins including FXII, complement components C1 to C9, and C1inh [1,6]. Since heparin can bind a variety of chemokines [7], important components of the immune system, it is of interest to evaluate if OSCS interacts with chemokines
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