title: S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis.
abstract: Multiple sclerosis (MS) pathology is characterized by neuroinflammation and demyelination. Recently, the inflammatory molecule S100B was identified in cerebrospinal fluid (CSF) and serum of MS patients. Although seen as an astrogliosis marker, lower/physiological levels of S100B are involved in oligodendrocyte differentiation/maturation. Nevertheless, increased S100B levels released upon injury may induce glial reactivity and oligodendrocyte demise, exacerbating tissue damage during an MS episode or delaying the following remyelination. Here, we aimed to unravel the functional role of S100B in the pathogenesis of MS. Elevated S100B levels were detected in the CSF of relapsing-remitting MS patients at diagnosis. Active demyelinating MS lesions showed increased expression of S100B and its receptor, the receptor for advanced glycation end products (RAGE), in the lesion area, while chronic active lesions displayed increased S100B in demyelinated areas with lower expression of RAGE in the rim. Interestingly, reactive astrocytes were identified as the predominant cellular source of S100B, whereas RAGE was expressed by activated microglia/macrophages. Using an ex vivo demyelinating model, cerebral organotypic slice cultures treated with lysophosphatidylcholine (LPC), we observed a marked elevation of S100B upon demyelination, which co-localized mostly with astrocytes. Inhibition of S100B action using a directed antibody reduced LPC-induced demyelination, prevented astrocyte reactivity and abrogated the expression of inflammatory and inflammasome-related molecules. Overall, high S100B expression in MS patient samples suggests its usefulness as a diagnostic biomarker for MS, while the beneficial outcome of its inhibition in our demyelinating model indicates S100B as an emerging therapeutic target in MS.
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Barateiro
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal.
authors.forename: Vera
authors.initials: V
authors.lastname: Afonso
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal.
authors.forename: Gisela
authors.initials: G
authors.lastname: Santos
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal.
authors.forename: João José
authors.initials: JJ
authors.lastname: Cerqueira
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal.|Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal.
authors.forename: Dora
authors.initials: D
authors.lastname: Brites
authors.affiliation: Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal. amaf@ff.ulisboa.pt.|Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal. amaf@ff.ulisboa.pt.
authors.forename: Adelaide
authors.initials: A
authors.lastname: Fernandes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D003711:Demyelinating Diseases / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D058990:Molecular Targeted Therapy; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009500:Neutralization Tests; D064568:S100 Calcium Binding Protein beta Subunit / Q000097:blood* / Q000134:cerebrospinal fluid*; D066127:White Matter / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D000951:Antigens, Neoplasm; D015415:Biomarkers; D016207:Cytokines; D058847:Inflammasomes; D008244:Lysophosphatidylcholines; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D064568:S100 Calcium Binding Protein beta Subunit; C579160:S100B protein, human; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases
keywords: Cerebellar organotypic slice cultures; Demyelination; Glial inflammatory response; Human samples; Multiple sclerosis; S100B