J Neuroinflammation. 2022 Jan 06;19(1):9. doi: 10.1186/s12974-021-02374-x.

Anti-inflammatory role of GM1 and other gangliosides on microglia.

Journal of neuroinflammation

Danny Galleguillos, Qian Wang, Noam Steinberg, Asifa Zaidi, Gaurav Shrivastava, Kamaldeep Dhami, Gour C Daskhan, Edward N Schmidt, Zoë Dworsky-Fried, Fabrizio Giuliani, Matthew Churchward, Christopher Power, Kathryn Todd, Anna Taylor, Matthew S Macauley, Simonetta Sipione

PMID: 34991625 DOI: 10.1186/s12974-021-02374-x

Abstract

BACKGROUND: Gangliosides are glycosphingolipids highly enriched in the brain, with important roles in cell signaling, cell-to-cell communication, and immunomodulation. Genetic defects in the ganglioside biosynthetic pathway result in severe neurodegenerative diseases, while a partial decrease in the levels of specific gangliosides was reported in Parkinson's disease and Huntington's disease. In models of both diseases and other conditions, administration of GM1-one of the most abundant gangliosides in the brain-provides neuroprotection. Most studies have focused on the direct neuroprotective effects of gangliosides on neurons, but their role in other brain cells, in particular microglia, is not known. In this study we investigated the effects of exogenous ganglioside administration and modulation of endogenous ganglioside levels on the response of microglia to inflammatory stimuli, which often contributes to initiation or exacerbation of neurodegeneration.

METHODS: In vitro studies were performed using BV2 cells, mouse, rat, and human primary microglia cultures. Modulation of microglial ganglioside levels was achieved by administration of exogenous gangliosides, or by treatment with GENZ-123346 and L-t-PDMP, an inhibitor and an activator of glycolipid biosynthesis, respectively. Response of microglia to inflammatory stimuli (LPS, IL-1β, phagocytosis of latex beads) was measured by analysis of gene expression and/or secretion of pro-inflammatory cytokines. The effects of GM1 administration on microglia activation were also assessed in vivo in C57Bl/6 mice, following intraperitoneal injection of LPS.

RESULTS: GM1 decreased inflammatory microglia responses in vitro and in vivo, even when administered after microglia activation. These anti-inflammatory effects depended on the presence of the sialic acid residue in the GM1 glycan headgroup and the presence of a lipid tail. Other gangliosides shared similar anti-inflammatory effects in in vitro models, including GD3, GD1a, GD1b, and GT1b. Conversely, GM3 and GQ1b displayed pro-inflammatory activity. The anti-inflammatory effects of GM1 and other gangliosides were partially reproduced by increasing endogenous ganglioside levels with L-t-PDMP, whereas inhibition of glycolipid biosynthesis exacerbated microglial activation in response to LPS stimulation.

CONCLUSIONS: Our data suggest that gangliosides are important modulators of microglia inflammatory responses and reveal that administration of GM1 and other complex gangliosides exerts anti-inflammatory effects on microglia that could be exploited therapeutically.

© 2022. The Author(s).

Keywords: BV2 cells; GENZ-123346; GM1; Gangliosides; Inflammation; LPS; Liposomes; L–t-PDMP; Microglia

References

1. Frost JL, Schafer DP. Microglia: architects of the developing nervous system. Trends Cell Biol. 2016;26(8):587–97. - PubMed
2. Li Q, Barres BA. Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol. 2018;18(4):225–42. - PubMed
3. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314–8. - PubMed
4. Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J, Ishii M, et al. Layer V cortical neurons require microglial support for survival during postnatal development. Nat Neurosci. 2013;16(5):543–51. - PubMed
5. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. 2013;155(7):1596–609. - PubMed
6. Cunningham CL, Martinez-Cerdeno V, Noctor SC. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci. 2013;33(10):4216–33. - PubMed
7. Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 2009;27:119–45. - PubMed
8. Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Rev Neurol. 2010;6(4):193–201. - PubMed
9. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388–405. - PubMed
10. Crotti A, Glass CK. The choreography of neuroinflammation in Huntington’s disease. Trends Immunol. 2015;36(6):364–73. - PubMed
11. Bjorkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med. 2008;205(8):1869–77. - PubMed
12. McGeer PL, McGeer EG. Glial reactions in Parkinson’s disease. Mov Disord. 2008;23(4):474–83. - PubMed
13. More SV, Kumar H, Kim IS, Song SY, Choi DK. Cellular and molecular mediators of neuroinflammation in the pathogenesis of Parkinson’s disease. Mediators Inflamm. 2013;2013:952375. - PubMed
14. Lucin KM, Wyss-Coray T. Immune activation in brain aging and neurodegeneration: too much or too little? Neuron. 2009;64(1):110–22. - PubMed
15. Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol. 2014;14(7):463–77. - PubMed
16. Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science. 2016;353(6301):777–83. - PubMed
17. Zhou JY, Oswald DM, Oliva KD, Kreisman LSC, Cobb BA. The glycoscience of immunity. Trends Immunol. 2018;39(7):523–35. - PubMed
18. Schnaar RL, Kinoshita T, et al. Glycosphingolipids. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, et al., editors. Essentials of glycobiology. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2021. - PubMed
19. Copyright 2015–2017 by The Consortium of Glycobiology Editors, La Jolla, California. All rights reserved; 2015; p. 125–35. - PubMed
20. Fukuda M, Rutishauser U, Schnaar RL. Neuroglycobiology. New York: Oxford University Press; 2005. p. 229. - PubMed
21. Posse de Chaves E, Sipione S. Sphingolipids and gangliosides of the nervous system in membrane function and dysfunction. FEBS Lett. 2010;584(9):1748–59. - PubMed
22. Sipione SMJ, Galleguillos D, Steinberg N, Kadam V. Gangliosides in the brain: physiology, pathophysiology and therapeutic applications. Front Neurosci. 2020;14:1–24. - PubMed
23. Allende ML, Proia RL. Simplifying complexity: genetically resculpting glycosphingolipid synthesis pathways in mice to reveal function. Glycoconj J. 2014;31(9):613–22. - PubMed
24. Kracun I, Rosner H, Drnovsek V, Vukelic Z, Cosovic C, Trbojevic-Cepe M, et al. Gangliosides in the human brain development and aging. Neurochem Int. 1992;20(3):421–31. - PubMed
25. Mo L, Ren Q, Duchemin AM, Neff NH, Hadjiconstantinou M. GM1 and ERK signaling in the aged brain. Brain Res. 2005;1054(2):125–34. - PubMed
26. Palestini P, Masserini M, Sonnino S, Giuliani A, Tettamanti G. Changes in the ceramide composition of rat forebrain gangliosides with age. J Neurochem. 1990;54(1):230–5. - PubMed
27. Segler-Stahl K, Webster JC, Brunngraber EG. Changes in the concentration and composition of human brain gangliosides with aging. Gerontology. 1983;29(3):161–8. - PubMed
28. Maglione V, Marchi P, Di Pardo A, Lingrell S, Horkey M, Tidmarsh E, et al. Impaired ganglioside metabolism in Huntington’s disease and neuroprotective role of GM1. J Neurosci. 2010;30(11):4072–80. - PubMed
29. Desplats PA, Denny CA, Kass KE, Gilmartin T, Head SR, Sutcliffe JG, et al. Glycolipid and ganglioside metabolism imbalances in Huntington’s disease. Neurobiol Dis. 2007;27(3):265–77. - PubMed
30. Wu G, Lu ZH, Kulkarni N, Ledeen RW. Deficiency of ganglioside GM1 correlates with Parkinson’s disease in mice and humans. J Neurosci Res. 2012;90(10):1997–2008. - PubMed
31. Schneider JS. Altered expression of genes involved in ganglioside biosynthesis in substantia Nigra neurons in Parkinson’s disease. PLoS ONE. 2018;13(6):e0199189. - PubMed
32. Blennow K, Davidsson P, Wallin A, Fredman P, Gottfries CG, Karlsson I, et al. Gangliosides in cerebrospinal fluid in ‘probable Alzheimer’s disease.’ Arch Neurol. 1991;48(10):1032–5. - PubMed
33. Blennow K, Davidsson P, Wallin A, Fredman P, Gottfries CG, Mansson JE, et al. Differences in cerebrospinal fluid gangliosides between “probable Alzheimer’s disease” and normal aging. Aging (Milano). 1992;4(4):301–6. - PubMed
34. Alpaugh M GD, Forero J, Morales LC, Lackey S, Kar P, Di Pardo A, Holt A, Kerr B, Todd K, Baker GB, Fouad K, Sipione S. Therapeutic and disease-modifying effects of ganglioside GM1 in mouse models of Huntington’s disease. Submitted2017. - PubMed
35. Magistretti PJ, Geisler FH, Schneider JS, Li PA, Fiumelli H, Sipione S. Gangliosides: treatment avenues in neurodegenerative disease. Front Neurol. 2019;10:859. - PubMed
36. Pope-Coleman A, Schneider JS. Effects of chronic GM1 ganglioside treatment on cognitieve and motor deficits in a slowly progressing model of parkinsonism in non-human primates. Restor Neurol Neurosci. 1998;12(4):255–66. - PubMed
37. Schneider JS. GM1 ganglioside in the treatment of Parkinson’s disease. Ann N Y Acad Sci. 1998;845:363–73. - PubMed
38. Schneider JS, Aras R, Williams CK, Koprich JB, Brotchie JM, Singh V. GM1 ganglioside modifies alpha-synuclein toxicity and is neuroprotective in a rat alpha-synuclein model of Parkinson’s disease. Sci Rep. 2019;9(1):8362. - PubMed
39. Alpaugh M, Galleguillos D, Forero J, Morales LC, Lackey SW, Kar P, et al. Disease-modifying effects of ganglioside GM1 in Huntington’s disease models. EMBO Mol Med. 2017;9(11):1537–57. - PubMed
40. Di Pardo A, Maglione V, Alpaugh M, Horkey M, Atwal RS, Sassone J, et al. Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice. Proc Natl Acad Sci U S A. 2012;109(9):3528–33. - PubMed
41. Ohmi Y, Tajima O, Ohkawa Y, Yamauchi Y, Sugiura Y, Furukawa K, et al. Gangliosides are essential in the protection of inflammation and neurodegeneration via maintenance of lipid rafts: elucidation by a series of ganglioside-deficient mutant mice. J Neurochem. 2011;116(5):926–35. - PubMed
42. Ohmi Y, Ohkawa Y, Tajima O, Sugiura Y, Furukawa K, Furukawa K. Ganglioside deficiency causes inflammation and neurodegeneration via the activation of complement system in the spinal cord. J Neuroinflammation. 2014;11:61. - PubMed
43. Gong G, Yin L, Yuan L, Sui D, Sun Y, Fu H, et al. Ganglioside GM1 protects against high altitude cerebral edema in rats by suppressing the oxidative stress and inflammatory response via the PI3K/AKT-Nrf2 pathway. Mol Immunol. 2018;95:91–8. - PubMed
44. Saura J, Tusell JM, Serratosa J. High-yield isolation of murine microglia by mild trypsinization. Glia. 2003;44(3):183–9. - PubMed
45. Walsh JG, Reinke SN, Mamik MK, McKenzie BA, Maingat F, Branton WG, et al. Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS. Retrovirology. 2014;11:35. - PubMed
46. Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F. Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol. 1990;27(2–3):229–37. - PubMed
47. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3(7):RESEARCH0034. - PubMed
48. Henn A, Lund S, Hedtjärn M, Schrattenholz A, Pörzgen P, Leist M. The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. Altex. 2009;26(2):83–94. - PubMed
49. Franklin TC, Xu C, Duman RS. Depression and sterile inflammation: essential role of danger associated molecular patterns. Brain Behav Immun. 2018;72:2–13. - PubMed
50. Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, et al. High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol. 2006;290(3):C917–24. - PubMed
51. Azam S, Jakaria M, Kim IS, Kim J, Haque ME, Choi DK. Regulation of toll-like receptor (TLR) signaling pathway by polyphenols in the treatment of age-linked neurodegenerative diseases: focus on TLR4 signaling. Front Immunol. 2019;10:1000. - PubMed
52. Rauvala H. Monomer-micelle transition of the ganglioside GM1 and the hydrolysis by clostridium perfringens neuraminidase. Eur J Biochem. 1979;97(2):555–64. - PubMed
53. Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, et al. New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci U S A. 2016;113(12):E1738–46. - PubMed
54. Hovens IB, Nyakas C, Schoemaker RG. A novel method for evaluating microglial activation using ionized calcium-binding adaptor protein-1 staining: cell body to cell size ratio. Neuroimmunol Neuroinflammation. 2014;1:82–8. - PubMed
55. García-Magro N, Martin YB, Palomino-Antolin A, Egea J, Negredo P, Avendaño C. Multiple morphometric assessment of microglial cells in deafferented spinal trigeminal nucleus. Front Neuroanat. 2019;13:103. - PubMed
56. Lynch MA. The multifaceted profile of activated microglia. Mol Neurobiol. 2009;40(2):139–56. - PubMed
57. Taylor AMW, Mehrabani S, Liu S, Taylor AJ, Cahill CM. Topography of microglial activation in sensory- and affect-related brain regions in chronic pain. J Neurosci Res. 2017;95(6):1330–5. - PubMed
58. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918–34. - PubMed
59. Voet S, Srinivasan S, Lamkanfi M, van Loo G. Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Mol Med. 2019;11(6). - PubMed
60. Rajamaki K, Lappalainen J, Oorni K, Valimaki E, Matikainen S, Kovanen PT, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS ONE. 2010;5(7):e11765. - PubMed
61. Kudo N, Kumagai K, Tomishige N, Yamaji T, Wakatsuki S, Nishijima M, et al. Structural basis for specific lipid recognition by CERT responsible for nonvesicular trafficking of ceramide. Proc Natl Acad Sci U S A. 2008;105(2):488–93. - PubMed
62. Fantini J, Barrantes FJ. Sphingolipid/cholesterol regulation of neurotransmitter receptor conformation and function. Biochim Biophys Acta. 2009;1788(11):2345–61. - PubMed
63. Inokuchi J, Usuki S, Jimbo M. Stimulation of glycosphingolipid biosynthesis by L-threo-1-phenyl-2-decanoylamino-1-propanol and its homologs in B16 melanoma cells. J Biochem. 1995;117(4):766–73. - PubMed
64. Simpson MA, Cross H, Proukakis C, Priestman DA, Neville DC, Reinkensmeier G, et al. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet. 2004;36(11):1225–9. - PubMed
65. Fragaki K, Ait-El-Mkadem S, Chaussenot A, Gire C, Mengual R, Bonesso L, et al. Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency. Eur J Hum Genet. 2013;21(5):528–34. - PubMed
66. Boccuto L, Aoki K, Flanagan-Steet H, Chen CF, Fan X, Bartel F, et al. A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation. Hum Mol Genet. 2014;23(2):418–33. - PubMed
67. Wakil SM, Monies DM, Ramzan K, Hagos S, Bastaki L, Meyer BF, et al. Novel B4GALNT1 mutations in a complicated form of hereditary spastic paraplegia. Clin Genet. 2014;86(5):500–1. - PubMed
68. Harlalka GV, Lehman A, Chioza B, Baple EL, Maroofian R, Cross H, et al. Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis. Brain. 2013;136(Pt 12):3618–24. - PubMed
69. Boukhris A, Schule R, Loureiro JL, Lourenco CM, Mundwiller E, Gonzalez MA, et al. Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am J Hum Genet. 2013;93(1):118–23. - PubMed
70. Shayman JA. The design and clinical development of inhibitors of glycosphingolipid synthesis: will invention be the mother of necessity? Trans Am Clin Climatol Assoc. 2013;124:46–60. - PubMed
71. Oppenheimer S. GM1 ganglioside therapy in acute ischemic stroke. Stroke. 1990;21(5):825. - PubMed
72. Simon RP, Chen J, Graham SH. GM1 ganglioside treatment of focal ischemia: a dose-response and microdialysis study. J Pharmacol Exp Ther. 1993;265(1):24–9. - PubMed
73. Pope-Coleman A, Tinker JP, Schneider JS. Effects of GM1 ganglioside treatment on pre- and postsynaptic dopaminergic markers in the striatum of parkinsonian monkeys. Synapse. 2000;36(2):120–8. - PubMed
74. Schneider JS, Gollomp SM, Sendek S, Colcher A, Cambi F, Du W. A randomized, controlled, delayed start trial of GM1 ganglioside in treated Parkinson’s disease patients. J Neurol Sci. 2013;324(1–2):140–8. - PubMed
75. Ledeen RW, Wu G. Gangliosides, alpha-Synuclein, and Parkinson’s disease. Prog Mol Biol Transl Sci. 2018;156:435–54. - PubMed
76. Ledeen RW, Wu G. The multi-tasked life of GM1 ganglioside, a true factotum of nature. Trends Biochem Sci. 2015;40(7):407–18. - PubMed
77. Mocchetti I. Exogenous gangliosides, neuronal plasticity and repair, and the neurotrophins. Cell Mol Life Sci. 2005;62(19–20):2283–94. - PubMed
78. Kwan W, Trager U, Davalos D, Chou A, Bouchard J, Andre R, et al. Mutant huntingtin impairs immune cell migration in Huntington disease. J Clin Invest. 2012;122(12):4737–47. - PubMed
79. Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, Zuccato C, et al. Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci. 2014;17(4):513–21. - PubMed
80. Moller T. Neuroinflammation in Huntington’s disease. J Neural Transm. 2010;117(8):1001–8. - PubMed
81. Park JY, Kim HY, Jou I, Park SM. GM1 induces p38 and microtubule dependent ramification of rat primary microglia in vitro. Brain Res. 2008;1244:13–23. - PubMed
82. Min KJ, Pyo HK, Yang MS, Ji KA, Jou I, Joe EH. Gangliosides activate microglia via protein kinase C and NADPH oxidase. Glia. 2004;48(3):197–206. - PubMed
83. Min KJ, Yang MS, Jou I, Joe EH. Protein kinase A mediates microglial activation induced by plasminogen and gangliosides. Exp Mol Med. 2004;36(5):461–7. - PubMed
84. Pyo H, Joe E, Jung S, Lee SH, Jou I. Gangliosides activate cultured rat brain microglia. J Biol Chem. 1999;274(49):34584–9. - PubMed
85. Ziegler-Heitbrock HW, Kafferlein E, Haas JG, Meyer N, Strobel M, Weber C, et al. Gangliosides suppress tumor necrosis factor production in human monocytes. J Immunol. 1992;148(6):1753–8. - PubMed
86. Wang Y, Cui Y, Cao F, Qin Y, Li W, Zhang J. Ganglioside GD1a suppresses LPS-induced pro-inflammatory cytokines in RAW264.7 macrophages by reducing MAPKs and NF-kappaB signaling pathways through TLR4. Int Immunopharmacol. 2015;28(1):136–45. - PubMed
87. Shen W, Stone K, Jales A, Leitenberg D, Ladisch S. Inhibition of TLR activation and up-regulation of IL-1R-associated kinase-M expression by exogenous gangliosides. J Immunol. 2008;180(7):4425–32. - PubMed
88. Ariga T, Yu RK. GM1 inhibits amyloid beta-protein-induced cytokine release. Neurochem Res. 1999;24(2):219–26. - PubMed
89. Ariga T, Kiso M, Hasegawa A, Miyatake T. Gangliosides inhibit the release of interleukin-1beta in amyloid beta-protein-treated human monocytic cells. J Mol Neurosci. 2001;17(3):371–7. - PubMed
90. Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong J-S, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55(5):453–62. - PubMed
91. Kanazawa H, Ohsawa K, Sasaki Y, Kohsaka S, Imai Y. Macrophage/microglia-specific protein Iba1 enhances membrane ruffling and Rac activation via phospholipase C-gamma -dependent pathway. J Biol Chem. 2002;277(22):20026–32. - PubMed
92. Ohsawa K, Imai Y, Kanazawa H, Sasaki Y, Kohsaka S. Involvement of Iba1 in membrane ruffling and phagocytosis of macrophages/microglia. J Cell Sci. 2000;113(Pt 17):3073–84. - PubMed
93. Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, et al. Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci Lett. 1994;180(2):147–50. - PubMed
94. Hull M, Berger M, Volk B, Bauer J. Occurrence of interleukin-6 in cortical plaques of Alzheimer’s disease patients may precede transformation of diffuse into neuritic plaques. Ann N Y Acad Sci. 1996;777:205–12. - PubMed
95. Rothaug M, Becker-Pauly C, Rose-John S. The role of interleukin-6 signaling in nervous tissue. Biochim Biophys Acta. 2016;1863(6 Pt A):1218–27. - PubMed
96. Wagner JA. Is IL-6 both a cytokine and a neurotrophic factor? J Exp Med. 1996;183(6):2417–9. - PubMed
97. Akaneya Y, Takahashi M, Hatanaka H. Interleukin-1 beta enhances survival and interleukin-6 protects against MPP+ neurotoxicity in cultures of fetal rat dopaminergic neurons. Exp Neurol. 1995;136(1):44–52. - PubMed
98. Hirota H, Kiyama H, Kishimoto T, Taga T. Accelerated nerve regeneration in mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma. J Exp Med. 1996;183(6):2627–34. - PubMed
99. Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, et al. Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science. 1997;278(5337):477–83. - PubMed
100. Chucair-Elliott AJ, Conrady C, Zheng M, Kroll CM, Lane TE, Carr DJ. Microglia-induced IL-6 protects against neuronal loss following HSV-1 infection of neural progenitor cells. Glia. 2014;62(9):1418–34. - PubMed
101. Cavaillon JM, Fitting C, Hauttecoeur B, Haeffner-Cavaillon N. Inhibition by gangliosides of the specific binding of lipopolysaccharide (LPS) to human monocytes prevents LPS-induced interleukin-1 production. Cell Immunol. 1987;106(2):293–303. - PubMed
102. Jeng KC, Chen TL, Lan JL. Gangliosides suppression of murine lymphoproliferation and interleukin 1 production. Immunol Lett. 1988;19(4):335–40. - PubMed
103. Jou I, Lee JH, Park SY, Yoon HJ, Joe EH, Park EJ. Gangliosides trigger inflammatory responses via TLR4 in brain glia. Am J Pathol. 2006;168(5):1619–30. - PubMed
104. Boyd CR, Orr SJ, Spence S, Burrows JF, Elliott J, Carroll HP, et al. Siglec-E is up-regulated and phosphorylated following lipopolysaccharide stimulation in order to limit TLR-driven cytokine production. J Immunol. 2009;183(12):7703–9. - PubMed
105. Macauley MS, Crocker PR, Paulson JC. Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol. 2014;14(10):653–66. - PubMed
106. Chen G-Y, Brown NK, Wu W, Khedri Z, Yu H, Chen X, et al. Broad and direct interaction between TLR and Siglec families of pattern recognition receptors and its regulation by Neu1. eLife. 2014;3. - PubMed
107. Chiricozzi E, Pomè DY, Maggioni M, Di Biase E, Parravicini C, Palazzolo L, et al. Role of the GM1 ganglioside oligosaccharide portion in the TrkA-dependent neurite sprouting in neuroblastoma cells. J Neurochem. 2017;143(6):645–59. - PubMed
108. Sonnino S, Mauri L, Chigorno V, Prinetti A. Gangliosides as components of lipid membrane domains. Glycobiology. 2007;17(1):1R-13R. - PubMed
109. van der Bruggen T, Nijenhuis S, van Raaij E, Verhoef J, van Asbeck BS. Lipopolysaccharide-induced tumor necrosis factor alpha production by human monocytes involves the raf-1/MEK1-MEK2/ERK1-ERK2 pathway. Infect Immun. 1999;67(8):3824–9. - PubMed
110. Gais P, Tiedje C, Altmayr F, Gaestel M, Weighardt H, Holzmann B. TRIF signaling stimulates translation of TNF-α mRNA via prolonged activation of MK2. J Immunol. 2010;184(10):5842–8. - PubMed
111. Mazumder B, Li X, Barik S. Translation control: a multifaceted regulator of inflammatory response. J Immunol. 2010;184(7):3311–9. - PubMed

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