Brain inflammation induces alterations in glycosaminoglycan metabolism and subsequent changes in CS-4S and hyaluronic acid

Rafaela V Silva; Karina Biskup; Jessica Katherine Zabala-Jouvin; Clara S Batzdorf; Caroline Stellmach; Anna S Morr; Ingolf Sack; Antje Ludwig; Véronique Blanchard; Carmen Infante-Duarte

doi:10.1016/j.ijbiomac.2023.123214

Brain inflammation induces alterations in glycosaminoglycan metabolism and subsequent changes in CS-4S and hyaluronic acid

Int J Biol Macromol. 2023 Mar 1:230:123214. doi: 10.1016/j.ijbiomac.2023.123214. Epub 2023 Jan 10.

Affiliations

¹ Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; Charité - Universitätsmedizin Berlin, Einstein Center for Neurosciences Berlin, Berlin, Germany.
² Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Berlin, Germany; Medical School Berlin, Department of Human Medicine, Berlin, Germany.
³ Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Berlin, Germany; Institute of Chemistry, Freie Universität Berlin, Berlin, Germany.
⁴ Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
⁵ Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Berlin, Germany; Institute of Biology, Freie Universität Berlin, Berlin, Germany.
⁶ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiology, Berlin, Germany.
⁷ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Department of Cardiology and Angiology, Berlin, Germany; DZHK (German Center for Cardiovascular Research), Partner Site, Berlin, Germany.
⁸ Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Electronic address: carmen.infante@charite.de.

PMID: 36634800
DOI: 10.1016/j.ijbiomac.2023.123214

Abstract

It remains uncertain how brain glycosaminoglycans (GAGs) contribute to the progression of inflammatory disorders like multiple sclerosis (MS). We investigated here neuroinflammation-mediated changes in GAG composition and metabolism using the mouse model of experimental autoimmune encephalomyelitis (EAE) and sham-immunized mice as controls. Cerebellum, mid- and forebrain at different EAE phases were investigated using gene expression analysis (microarray and RT-qPCR) as well as HPLC quantification of CS and hyaluronic acid (HA). The cerebellum was the most affected brain region showing a downregulation of Bcan, Cspg5, and an upregulation of Dse, Gusb, Hexb, Dcn and Has2 at peak EAE. Upregulation of genes involved in GAG degradation as well as synthesis of HA and decorin persisted from onset to peak, and diminished at remission, suggesting a severity-related decrease in CS and increments in HA. Relative disaccharide quantification confirmed a 3.6 % reduction of CS-4S at peak and a normalization during remission, while HA increased in both phases by 26.1 % and 17.6 %, respectively. Early inflammatory processes led to altered GAG metabolism in early EAE stages and subsequent partially reversible changes in CS-4S and in HA. Targeting early modifications in CS could potentially mitigate progression of EAE/MS.

Keywords: Chondroitin sulfate; Experimental autoimmune encephalomyelitis; Extracellular matrix; Glycosaminoglycans; Hyaluronic acid; Multiple sclerosis.

MeSH terms

Animals
Chondroitin Sulfates / metabolism
Encephalitis*
Encephalomyelitis, Autoimmune, Experimental* / genetics
Glycosaminoglycans / metabolism
Hyaluronic Acid / pharmacology
Mice
Multiple Sclerosis*

Substances

Hyaluronic Acid
Glycosaminoglycans
Chondroitin Sulfates