A sulfated disaccharide derived from chondroitin sulfate proteoglycan protects against inflammation-associated neurodegeneration.
Chondroitin sulfate proteoglycan (CSPG), a matrix protein that occurs naturally in the central nervous system (CNS), is considered to be a major inhibitor of axonal regeneration and is known to participate in activation of the inflammatory response. The degradation of CSPG by a specific enzyme, chondroitinase ABC, promotes repair. We postulated that a disaccharidic degradation product of this glycoprotein (CSPG-DS), generated following such degradation, participates in the modulation of the inflammatory responses and can, therefore, promote recovery in immune-induced neuropathologies of the CNS, such as experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune uveitis (EAU). In these pathologies, the dramatic increase in T cells infiltrating the CNS is far in excess of the numbers needed for regular maintenance. Here, we show that CSPG-DS markedly alleviated the clinical symptoms of EAE and protected against the neuronal loss in EAU. The last effect was associated with a reduction in the numbers of infiltrating T cells and marked microglia activation. This is further supported by our in vitro results indicating that CSPG-DS attenuated T cell motility and decreased secretion of the cytokines interferon-gamma and tumor necrosis factor-alpha. Mechanistically, these effects are associated with an increase in SOCS-3 levels and a decrease in NF-kappaB. Our results point to a potential therapeutic modality, in which a compound derived from an endogenous CNS-resident molecule, known for its destructive role in CNS recovery, might be helpful in overcoming inflammation-induced neurodegenerative conditions.
Rolls
Asya
A
Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.
Cahalon
Liora
L
Bakalash
Sharon
S
Avidan
Hila
H
Lider
Ofer
O
Schwartz
Michal
M
D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001327:Autoimmune Diseases / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002448:Cell Adhesion; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D011508:Chondroitin Sulfate Proteoglycans / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004187:Disaccharides / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy / Q000517:prevention & control; D007155:Immunologic Factors / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014605:Uveitis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011508:Chondroitin Sulfate Proteoglycans; D016207:Cytokines; D004187:Disaccharides; D007155:Immunologic Factors; D016328:NF-kappa B; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma