N-acetylglucosamine inhibits inflammation and neurodegeneration markers in multiple sclerosis: a mechanistic trial.
Chronic-active brain inflammation
Multiple sclerosis
N-acetylglucosamine
N-glycan branching
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
13 Sep 2023
13 Sep 2023
Historique:
received:
01
08
2023
accepted:
07
09
2023
medline:
15
9
2023
pubmed:
14
9
2023
entrez:
13
9
2023
Statut:
epublish
Résumé
In the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduces episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans, age-associated increases in endogenous GlcNAc promote T cell senescence. An open label dose-escalation mechanistic trial of oral GlcNAc at 6 g (n = 18) and 12 g (n = 16) for 4 weeks was performed in MS patients on glatiramer acetate and not in relapse from March 2016 to December 2019 to assess changes in serum GlcNAc, lymphocyte N-glycosylation and inflammatory markers. Post-hoc analysis examined changes in serum neurofilament light chain (sNfL) as well as neurological disability via the Expanded Disability Status Scale (EDSS). Prior to GlcNAc therapy, high serum levels of the inflammatory cytokines IFNγ, IL-17 and IL-6 associated with reduced baseline levels of a marker of endogenous serum GlcNAc. Oral GlcNAc therapy was safe, raised serum levels and modulated N-glycan branching in lymphocytes. Glatiramer acetate reduces T Oral GlcNAc inhibits inflammation and neurodegeneration markers in MS patients despite concurrent immunomodulation by glatiramer acetate. Blinded studies are required to investigate GlcNAc's potential to control residual brain inflammation, myelin repair and neurodegeneration in MS.
Sections du résumé
BACKGROUND
BACKGROUND
In the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduces episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans, age-associated increases in endogenous GlcNAc promote T cell senescence.
OBJECTIVES AND METHODS
OBJECTIVE
An open label dose-escalation mechanistic trial of oral GlcNAc at 6 g (n = 18) and 12 g (n = 16) for 4 weeks was performed in MS patients on glatiramer acetate and not in relapse from March 2016 to December 2019 to assess changes in serum GlcNAc, lymphocyte N-glycosylation and inflammatory markers. Post-hoc analysis examined changes in serum neurofilament light chain (sNfL) as well as neurological disability via the Expanded Disability Status Scale (EDSS).
RESULTS
RESULTS
Prior to GlcNAc therapy, high serum levels of the inflammatory cytokines IFNγ, IL-17 and IL-6 associated with reduced baseline levels of a marker of endogenous serum GlcNAc. Oral GlcNAc therapy was safe, raised serum levels and modulated N-glycan branching in lymphocytes. Glatiramer acetate reduces T
CONCLUSIONS
CONCLUSIONS
Oral GlcNAc inhibits inflammation and neurodegeneration markers in MS patients despite concurrent immunomodulation by glatiramer acetate. Blinded studies are required to investigate GlcNAc's potential to control residual brain inflammation, myelin repair and neurodegeneration in MS.
Identifiants
pubmed: 37705084
doi: 10.1186/s12974-023-02893-9
pii: 10.1186/s12974-023-02893-9
pmc: PMC10498575
doi:
Substances chimiques
Acetylglucosamine
V956696549
Interleukin-17
0
Glatiramer Acetate
5M691HL4BO
Interleukin-6
0
Cytokines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
209Subventions
Organisme : NCCIH NIH HHS
ID : R01AT007452
Pays : United States
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989;112(Pt 1):133–46.
pubmed: 2917275
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338(5):278–85.
pubmed: 9445407
Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015;14(2):183–93.
pubmed: 25772897
Henry RG, Shieh M, Okuda DT, Evangelista A, Gorno-Tempini ML, Pelletier D. Regional grey matter atrophy in clinically isolated syndromes at presentation. J Neurol Neurosurg Psychiatry. 2008;79(11):1236–44.
pubmed: 18469033
Zivadinov R, Havrdova E, Bergsland N, Tyblova M, Hagemeier J, Seidl Z, et al. Thalamic atrophy is associated with development of clinically definite multiple sclerosis. Radiology. 2013;268(3):831–41.
pubmed: 23613615
Steckova T, Hlustik P, Sladkova V, Odstrcil F, Mares J, Kanovsky P. Thalamic atrophy and cognitive impairment in clinically isolated syndrome and multiple sclerosis. J Neurol Sci. 2014;342(1–2):62–8.
pubmed: 24819917
Azevedo CJ, Overton E, Khadka S, Buckley J, Liu S, Sampat M, et al. Early CNS neurodegeneration in radiologically isolated syndrome. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e102.
pubmed: 25884012
pmcid: 4396526
Oberwahrenbrock T, Ringelstein M, Jentschke S, Deuschle K, Klumbies K, Bellmann-Strobl J, et al. Retinal ganglion cell and inner plexiform layer thinning in clinically isolated syndrome. Mult Scler. 2013;19(14):1887–95.
pubmed: 23702433
Popescu BF, Lucchinetti CF. Pathology of demyelinating diseases. Annu Rev Pathol. 2012;7:185–217.
pubmed: 22313379
Frischer JM, Weigand SD, Guo Y, Kale N, Parisi JE, Pirko I, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol. 2015;78(5):710–21.
pubmed: 26239536
pmcid: 4623970
Luchetti S, Fransen NL, van Eden CG, Ramaglia V, Mason M, Huitinga I. Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. Acta Neuropathol. 2018;135(4):511–28.
pubmed: 29441412
pmcid: 5978927
Kuhlmann T, Ludwin S, Prat A, Antel J, Bruck W, Lassmann H. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 2017;133(1):13–24.
pubmed: 27988845
Absinta M, Maric D, Gharagozloo M, Garton T, Smith MD, Jin J, et al. A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature. 2021;597(7878):709–14.
pubmed: 34497421
pmcid: 8719282
Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221–34.
pubmed: 28002679
Hauser SL, Belachew S, Kappos L. Ocrelizumab in primary progressive and relapsing multiple sclerosis. N Engl J Med. 2017;376(17):1694.
pubmed: 28445661
Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263–73.
pubmed: 29576505
Villoslada P, Steinman L. New targets and therapeutics for neuroprotection, remyelination and repair in multiple sclerosis. Expert Opin Investig Drugs. 2020;29(5):443–59.
pubmed: 32299268
Absinta M, Sati P, Schindler M, Leibovitch EC, Ohayon J, Wu T, et al. Persistent 7-tesla phase rim predicts poor outcome in new multiple sclerosis patient lesions. J Clin Invest. 2016;126(7):2597–609.
pubmed: 27270171
pmcid: 4922708
Absinta M, Sati P, Masuzzo F, Nair G, Sethi V, Kolb H, et al. Association of chronic active multiple sclerosis lesions with disability in vivo. JAMA Neurol. 2019;76(12):1474–83.
pubmed: 31403674
pmcid: 6692692
Elliott C, Wolinsky JS, Hauser SL, Kappos L, Barkhof F, Bernasconi C, et al. Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions. Mult Scler. 2019;25(14):1915–25.
pubmed: 30566027
Preziosa P, Pagani E, Meani A, Moiola L, Rodegher M, Filippi M, et al. Slowly expanding lesions predict 9-year multiple sclerosis disease progression. Neurol Neuroimmunol Neuroinflamm. 2022;9(2):e1139.
pubmed: 35105685
pmcid: 8808355
Lau KS, Partridge EA, Grigorian A, Silvescu CI, Reinhold VN, Demetriou M, et al. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell. 2007;129(1):123–34.
pubmed: 17418791
Grigorian A, Lee SU, Tian W, Chen IJ, Gao G, Mendelsohn R, et al. Control of T Cell-mediated autoimmunity by metabolite flux to N-glycan biosynthesis. J Biol Chem. 2007;282(27):20027–35.
pubmed: 17488719
Dennis JW, Nabi IR, Demetriou M. Metabolism, cell surface organization, and disease. Cell. 2009;139(7):1229–41.
pubmed: 20064370
pmcid: 3065826
Demetriou M, Granovsky M, Quaggin S, Dennis JW. Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature. 2001;409(6821):733–9.
pubmed: 11217864
Zhou RW, Mkhikian H, Grigorian A, Hong A, Chen D, Arakelyan A, et al. N-glycosylation bidirectionally extends the boundaries of thymocyte positive selection by decoupling Lck from Ca(2)(+) signaling. Nat Immunol. 2014;15(11):1038–45.
pubmed: 25263124
Mkhikian H, Mortales CL, Zhou RW, Khachikyan K, Wu G, Haslam SM, et al. Golgi self-correction generates bioequivalent glycans to preserve cellular homeostasis. eLife. 2016;5.
Araujo L, Khim P, Mkhikian H, Mortales CL, Demetriou M. Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation. eLife. 2017;6.
Chen IJ, Chen HL, Demetriou M. Lateral compartmentalization of T cell receptor versus CD45 by galectin-N-glycan binding and microfilaments coordinate basal and activation signaling. J Biol Chem. 2007;282(48):35361–72.
pubmed: 17897956
Grigorian A, Demetriou M. Mgat5 deficiency in T cells and experimental autoimmune encephalomyelitis. ISRN Neurol. 2011;2011: 374314.
pubmed: 22389815
pmcid: 3263545
Lee SU, Grigorian A, Pawling J, Chen IJ, Gao G, Mozaffar T, et al. N-glycan processing deficiency promotes spontaneous inflammatory demyelination and neurodegeneration. J Biol Chem. 2007;282(46):33725–34.
pubmed: 17855338
Mkhikian H, Hayama KL, Khachikyan K, Li C, Zhou RW, Pawling J, et al. Age-associated impairment of T cell immunity is linked to sex-dimorphic elevation of N-glycan branching. Nature Aging. 2022;2(3):231–42.
pubmed: 35528547
pmcid: 9075523
Morgan R, Gao G, Pawling J, Dennis JW, Demetriou M, Li B. N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation negatively regulates Th1 cytokine production by T cells. J Immunol. 2004;173(12):7200–8.
pubmed: 15585841
Mortales CL, Lee SU, Demetriou M. N-glycan branching is required for development of mature B cells. J Immunol. 2020;205(3):630–6.
pubmed: 32591389
Mortales CL, Lee SU, Manousadjian A, Hayama KL, Demetriou M. N-glycan branching decouples B cell innate and adaptive immunity to control inflammatory demyelination. J iScience. 2020;23(8):101380.
Starossom SC, Mascanfroni ID, Imitola J, Cao L, Raddassi K, Hernandez SF, et al. Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. Immunity. 2012;37(2):249–63.
pubmed: 22884314
pmcid: 3428471
Sy M, Brandt AU, Lee SU, Newton BL, Pawling J, Golzar A, et al. N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation. J Biol Chem. 2020;295(51):17413–24.
pubmed: 33453988
pmcid: 7762951
Pasquini LA, Millet V, Hoyos HC, Giannoni JP, Croci DO, Marder M, et al. Galectin-3 drives oligodendrocyte differentiation to control myelin integrity and function. Cell Death Differ. 2011;18(11):1746–56.
pubmed: 21566659
pmcid: 3190109
Ye Z, Marth JD. N-glycan branching requirement in neuronal and postnatal viability. Glycobiology. 2004;14(6):547–58.
pubmed: 15044398
Zhang Y, Yu X, Ichikawa M, Lyons JJ, Datta S, Lamborn IT, et al. Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment. J Allergy Clin Immunol. 2014;133(5):1400–9.
pubmed: 24589341
pmcid: 4016982
Li CF, Zhou RW, Mkhikian H, Newton BL, Yu Z, Demetriou M. Hypomorphic MGAT5 polymorphisms promote multiple sclerosis cooperatively with MGAT1 and interleukin-2 and 7 receptor variants. J Neuroimmunol. 2013;256:71.
pubmed: 23351704
pmcid: 4528623
Mkhikian H, Grigorian A, Li CF, Chen HL, Newton B, Zhou RW, et al. Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis. Nat Commun. 2011;2:334.
pubmed: 21629267
Brynedal B, Wojcik J, Esposito F, Debailleul V, Yaouanq J, Martinelli-Boneschi F, et al. MGAT5 alters the severity of multiple sclerosis. J Neuroimmunol. 2010;220(1–2):120–4.
pubmed: 20117844
Backer-Koduah P, Infante-Duarte C, Ivaldi F, Uccelli A, Bellmann-Strobl J, Wernecke KD, et al. Effect of vitamin D supplementation on N-glycan branching and cellular immunophenotypes in MS. Ann Clin Transl Neurol. 2020;7(9):1628–41.
pubmed: 32830462
pmcid: 7480923
Grigorian A, Araujo L, Naidu NN, Place D, Choudhury B, Demetriou M. N-acetylglucosamine inhibits T-helper 1 (Th1) / T-helper 17 (Th17) responses and treats experimental autoimmune encephalomyelitis. J Biol Chem. 2011;286:40133.
pubmed: 21965673
pmcid: 3220534
Brandt AU, Sy M, Bellmann-Strobl J, Newton BL, Pawling J, Zimmermann HG, et al. Association of a marker of n-acetylglucosamine with progressive multiple sclerosis and neurodegeneration. JAMA Neurol. 2021;78(7):842–52.
pubmed: 33970182
Siller N, Kuhle J, Muthuraman M, Barro C, Uphaus T, Groppa S, et al. Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis. Mult Scler. 2018;25:678.
pubmed: 29542376
Disanto G, Barro C, Benkert P, Naegelin Y, Schadelin S, Giardiello A, et al. Serum Neurofilament light: a biomarker of neuronal damage in multiple sclerosis. Ann Neurol. 2017;81(6):857–70.
pubmed: 28512753
pmcid: 5519945
Gupta SK. Intention-to-treat concept: a review. Perspect Clin Res. 2011;2(3):109–12.
pubmed: 21897887
pmcid: 3159210
Bai Z, Chen D, Wang L, Zhao Y, Liu T, Yu Y, et al. Cerebrospinal fluid and blood cytokines as biomarkers for multiple sclerosis: a systematic review and meta-analysis of 226 studies with 13,526 multiple sclerosis patients. Front Neurosci. 2019;13:1026.
pubmed: 31636528
pmcid: 6787166
Hulshof S, Montagne L, De Groot CJ, Van Der Valk P. Cellular localization and expression patterns of interleukin-10, interleukin-4, and their receptors in multiple sclerosis lesions. Glia. 2002;38(1):24–35.
pubmed: 11921201
Hu WT, Howell JC, Ozturk T, Gangishetti U, Kollhoff AL, Hatcher-Martin JM, et al. CSF cytokines in aging, multiple sclerosis, and dementia. Front Immunol. 2019;10:480.
pubmed: 30930904
pmcid: 6428695
Kallaur AP, Oliveira SR, Simao ANC, Alfieri DF, Flauzino T, Lopes J, et al. Cytokine profile in patients with progressive multiple sclerosis and its association with disease progression and disability. Mol Neurobiol. 2017;54(4):2950–60.
pubmed: 27023227
Thebault S, Abdoli M, Fereshtehnejad SM, Tessier D, Tabard-Cossa V, Freedman MS. Serum neurofilament light chain predicts long term clinical outcomes in multiple sclerosis. Sci Rep. 2020;10(1):10381.
pubmed: 32587320
pmcid: 7316736
Benkert P, Meier S, Schaedelin S, Manouchehrinia A, Yaldizli O, Maceski A, et al. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol. 2022;21(3):246–57.
pubmed: 35182510
Fernandez-Velasco JI, Kuhle J, Monreal E, Meca-Lallana V, Meca-Lallana J, Izquierdo G, et al. Effect of ocrelizumab in blood leukocytes of patients with primary progressive MS. Neurol Neuroimmunol Neuroinflamm. 2021;8(2):e940.
pubmed: 33408167
pmcid: 7862094
Bar-Or At G, Harp C, Bernasconi C, Bonati U, Cross AH, Fischer S, Gaetano L, Hauser SL, Hendricks R, Kappos L, Kuhle J, Leppert D, Model F, Koendgen H, Jia X, Herman A. Ocrelizumab treatment induces a sustained blood NfL reduction in patients with PPMS and RMS. ACTRIMS-ECTRIMS Meeting. 2020;11–13:2020.
Racke MK, Lovett-Racke AE, Karandikar NJ. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology. 2010;74(Suppl 1):S25-30.
pubmed: 20038760
Ireland SJ, Guzman AA, O’Brien DE, Hughes S, Greenberg B, Flores A, et al. The effect of glatiramer acetate therapy on functional properties of B cells from patients with relapsing-remitting multiple sclerosis. JAMA Neurol. 2014;71(11):1421–8.
pubmed: 25264704
pmcid: 4335670
Melnikov M, Sharanova S, Sviridova A, Rogovskii V, Murugina N, Nikolaeva A, et al. The influence of glatiramer acetate on Th17-immune response in multiple sclerosis. PLoS ONE. 2020;15(10): e0240305.
pubmed: 33126239
pmcid: 7599084
Cutter G, Rudick RA, de Moor C, Singh CM, Fisher E, Koster T, et al. Serum neurofilament light-chain levels and long-term treatment outcomes in relapsing-remitting multiple sclerosis patients: a post hoc analysis of the randomized CombiRx trial. Mult Scler J Exp Transl Clin. 2023;9(2):20552173231169464.
pubmed: 37139460
pmcid: 10150429
Levin RM, Krieger NN, Winzler RJ. Glucmsumine and acetylglucosamine tolerance in man. J Lab Clin Med. 1961;58:927–32.
pubmed: 14464574
Gaulden EC, Keating WC. The effect of intravenous N-Acetyl-D-glucosamine on the blood and urine sugar concentrations of normal subjects. Metab Clin Exp. 1964;13:466–72.
pubmed: 14169225
Salvatore S, Heuschkel R, Tomlin S, Davies SE, Edwards S, Walker-Smith JA, et al. A pilot study of N-acetyl glucosamine, a nutritional substrate for glycosaminoglycan synthesis, in paediatric chronic inflammatory bowel disease. Aliment Pharmacol Ther. 2000;14(12):1567–79.
pubmed: 11121904
Lee KY, Shibutani M, Takagi H, Arimura T, Takigami S, Uneyama C, et al. Subchronic toxicity study of dietary N-acetylglucosamine in F344 rats. Food Chem Toxicol. 2004;42(4):687–95.
pubmed: 15019194
Takahashi M, Inoue K, Yoshida M, Morikawa T, Shibutani M, Nishikawa A. Lack of chronic toxicity or carcinogenicity of dietary N-acetylglucosamine in F344 rats. Food Chem Toxicol. 2009;47(2):462–71.
pubmed: 19103248