Surfen, a proteoglycan binding agent, reduces inflammation but inhibits remyelination in murine models of Multiple Sclerosis

Abstract

Proteoglycans are promising therapeutic targets in Multiple Sclerosis (MS), because they regulate many aspects of the immune response. This was studied using surfen, an agent that binds both heparan sulphate proteoglycans (HSPGs) and chondroitin sulphate proteoglycans (CSPGs). Initial cell culture work on bone marrow derived macrophages (BMDMs) found that surfen reduced concentrations of the chemokines CCL2, CCL4 and CCL5, with reduced messenger (m)RNA expression for Tumor Necrosis Factor, IL-6, IL-1β and inducible nitric oxide synthase. These data were further explored using Experimental Autoimmune Encephalomyelitis (EAE) in mice. Surfen reduced clinical signs during EAE when administered from disease onset, and reduced infiltration by CD4 positive T cells and macrophages into the central nervous system. These mice also showed reduced mRNA expression for the chemokines CCL3 and CCL5, with reduced concentrations of CCL2, CCL3 and CCL5. During EAE, surfen treatment induced a persistent increase in Interleukin (IL)-4 concentrations which may enhance T helper 2 responses. During EAE, surfen treatment reduced mRNA expression for HSPGs (NDST1, agrin, syndecan-4, perlecan, serglycin, syndecan-1) and the CSPG versican. By contrast, surfen increased mRNA expression for the CSPG aggrecan, with no effect on neurocan. During EAE, significant positive correlations were found between mRNA expression and clinical score for syndecan-4, serglycin and syndecan-1 and a significant negative correlation for aggrecan. These correlations were absent in surfen treated mice. Repair in the later stages of MS involves remyelination, which was modeled by injecting lysolecithin (lysophosphatidylcholine, LPC) into mouse corpus callosum to create regions of demyelination. When surfen was injected 2 days after LPC, it delayed remyelination of the lesions, but had no effect when injected 7 days after LPC. The delayed remyelination was associated with local increases in CSPG expression. Therefore surfen suppresses inflammation but inhibits remyelination in these models. A mechanism in common may be increased CSPG expression.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0506-9) contains supplementary material, which is available to authorized users.

Molecular signature of extracellular matrix pathology in schizophrenia

“…Consistent with this finding, decreased SRGN expression has been reported in olfactory epithelium biopsy samples from subjects with SZ in association with visual learning and memory performance (Horiuchi et al., 2016). The expression of SRGN in the brain has not been well characterized, although it has been reported to increase in experimental autoimmune encephalomyelitis in mice and in glioma (Roy et al., 2017; Warford et al., 2018). In human amygdala, we found that SRGN protein product is observed as a distinctly punctate labelling within the neuron cytoplasm (Figure 8), suggesting a vesicular localization potentially consistent with SRGN expression in mast cells and hematopoietic cells, where it is located in cytoplasmic secretory granules, and binds to several cytokines and growth factors (Korpetinou et al., 2014; Sarrazin et al., 2011).…”

Role and Regulation of Mechanotransductive HIF-1α Stabilisation in Periodontal Ligament Fibroblasts

“…Because of their cellular location, focal adhesions play a role in signal transduction and have been suggested to function as mechanosensors in mature endothelial cells [ 54 ]. Surfen inhibits the interaction of proteoglycans with the focal adhesion complexes [ 55 ] and thereby truncated HIF-1α stabilisation due to mechanical strain in PDLF. These data strongly indicate an association between the interaction of proteoglycans with focal adhesion sites and mechanotransductive stabilisation of HIF-1α.…”

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

“…Indeed, some CSPGs (such as versican) are well known to inhibit remyelination, but others (such as aggrecan) may also be essential as protective factors during inflammation. In this respect, surfen, a compound known to bind the GAG side chains of proteoglycans with high affinity, has shown a protective effect in the EAE model, but a detrimental effect in the LPC model [100], probably due to a generalized increase in CSPG expression.…”