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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2022

Open Access 01-12-2022 | Research

Strawberry notch homolog 2 regulates the response to interleukin-6 in the central nervous system

Authors: Taylor E. Syme, Magdalena Grill, Emina Hayashida, Barney Viengkhou, Iain L. Campbell, Markus J. Hofer

Published in: Journal of Neuroinflammation | Issue 1/2022

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Abstract

Background

The cytokine interleukin-6 (IL-6) modulates a variety of inflammatory processes and, context depending, can mediate either pro- or anti-inflammatory effects. Excessive IL-6 signalling in the brain is associated with chronic inflammation resulting in neurodegeneration. Strawberry notch homolog 2 (Sbno2) is an IL-6-regulated gene whose function is largely unknown. Here we aimed to address this issue by investigating the impact of Sbno2 disruption in mice with IL-6-mediated neuroinflammation.

Methods

Mice with germline disruption of Sbno2 (Sbno2−/−) were generated and crossed with transgenic mice with chronic astrocyte production of IL-6 (GFAP-IL6). Phenotypic, molecular and transcriptomic analyses were performed on tissues and primary cell cultures to clarify the role of SBNO2 in IL-6-mediated neuroinflammation.

Results

We found Sbno2−/− mice to be viable and overtly normal. By contrast GFAP-IL6 × Sbno2−/− mice had more severe disease compared with GFAP-IL6 mice. This was evidenced by exacerbated neuroinflammation and neurodegeneration and enhanced IL-6-responsive gene expression. Cell culture experiments on primary astrocytes from Sbno2−/− mice further showed elevated and sustained transcript levels of a number of IL-6 stimulated genes. Notably, despite enhanced disease in vivo and gene expression both in vivo and in vitro, IL-6-stimulated gp130 pathway activation was reduced when Sbno2 is disrupted.

Conclusion

Based on these results, we propose a role for SBNO2 as a novel negative feedback regulator of IL-6 that restrains the excessive inflammatory actions of this cytokine in the brain.
Appendix
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Literature
1.
Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878–88.PubMedCrossRef
2.
Ley EJ, Clond MA, Singer MB, Shouhed D, Salim A. IL6 deficiency affects function after traumatic brain injury. J Surg Res. 2011;170(2):253–6.PubMedCrossRef
3.
Al-Obaidi MMJ, Desa MNM. Mechanisms of blood brain barrier disruption by different types of bacteria, and bacterial–host interactions facilitate the bacterial pathogen invading the brain. Cell Mol Neurobiol. 2018;38(7):1349–68.PubMedCrossRef
4.
Tarkowski E, Rosengren L, Blomstrand C, Wikkelso C, Jensen C, Ekholm S, et al. Early intrathecal production of interleukin-6 predicts the size of brain lesion in stroke. Stroke. 1995;26(8):1393–8.PubMedCrossRef
5.
Fujihara K, Bennett JL, de Seze J, Haramura M, Kleiter I, Weinshenker BG, et al. Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology. Neurol Neuroimmunol Neuroinflamm. 2020;7(5): e841.PubMedPubMedCentralCrossRef
6.
Maimone D, Guazzi GC, Annunziata P. IL-6 detection in multiple sclerosis brain. J Neurol Sci. 1997;146(1):59–65.PubMedCrossRef
7.
Escrig A, Canal C, Sanchis P, Fernández-Gayol O, Montilla A, Comes G, et al. IL-6 trans-signaling in the brain influences the behavioral and physio-pathological phenotype of the Tg2576 and 3xTgAD mouse models of Alzheimer’s disease. Brain Behav Immun. 2019;82:145–59.PubMedCrossRef
8.
Bolin LM, Strycharska-Orczyk I, Murray R, Langston JW, Di Monte D. Increased vulnerability of dopaminergic neurons in MPTP-lesioned interleukin-6 deficient mice. J Neurochem. 2002;83(1):167–75.PubMedCrossRef
9.
Sekizawa T, Openshaw H, Ohbo K, Sugamura K, Itoyama Y, Niland JC. Cerebrospinal fluid interleukin 6 in amyotrophic lateral sclerosis: immunological parameter and comparison with inflammatory and non-inflammatory central nervous system diseases. J Neurol Sci. 1998;154(2):194–9.PubMedCrossRef
10.
West AJ, Tsui V, Stylli SS, Nguyen HPT, Morokoff AP, Kaye AH, et al. The role of interleukin-6-STAT3 signalling in glioblastoma (Review). Oncol Lett. 2018;16(4):4095–104.PubMedPubMedCentral
11.
Rothaug M, Becker-Pauly C, Rose-John S. The role of interleukin-6 signaling in nervous tissue. Biochim Biophys Acta. 2016;1863(6, Part A):1218–27.PubMedCrossRef
12.
Spooren A, Kolmus K, Laureys G, Clinckers R, De Keyser J, Haegeman G, et al. Interleukin-6, a mental cytokine. Brain Res Rev. 2011;67(1–2):157–83.PubMedCrossRef
13.
Campbell IL, Erta M, Lim S, Frausto R, May U, Rose-John S, et al. Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain. J Neurosci. 2014;34(7):2503–13.PubMedPubMedCentralCrossRef
14.
Kaur S, Bansal Y, Kumar R, Bansal G. A panoramic review of IL-6: structure, pathophysiological roles and inhibitors. Bioorg Med Chem. 2020;28(5): 115327.PubMedCrossRef
15.
Sanz E, Hofer MJ, Unzeta M, Campbell IL. Minimal role for STAT1 in interleukin-6 signaling and actions in the murine brain. Glia. 2008;56(2):190–9.PubMedCrossRef
16.
Campbell IL, Abraham CR, Masliah E, Kemper P, Inglis JD, Oldstone M, et al. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci USA. 1993;90(21):10061–5.PubMedPubMedCentralCrossRef
17.
Campbell IL. Structural and functional impact of the transgenic expression of cytokines in the CNS. Ann N Y Acad Sci. 1998;840(1):83–96.PubMedCrossRef
18.
Chiang C-S, Stalder A, Samimi A, Campbell IL. Reactive gliosis as a consequence of interleukin-6 expression in the brain: studies in transgenic mice. Dev Neurosci. 1994;16(3–4):212–21.PubMedCrossRef
19.
Brett FM, Mizisin AP, Powell HC, Campbell IL. Evolution of neuropathologic abnormalities associated with blood-brain barrier breakdown in transgenic mice expressing interleukin-6 in astrocytes. J Neuropathol Exp Neurol. 1995;54(6):766–75.PubMedCrossRef
20.
Quintana A, Müller M, Frausto RF, Ramos R, Getts DR, Sanz E, et al. Site-specific production of IL-6 in the central nervous system retargets and enchances the inflammatory response in experimental autoimmune encephalomyelitis. J Immunol. 2009;183:2079–88.PubMedCrossRef
21.
Tsuda L, Nagaraj R, Zipursky SL, Banerjee U. An EGFR/Ebi/Sno pathway promotes delta expression by inactivating Su(H)/SMRTER repression during inductive notch signaling. Cell. 2002;110(5):625–37.PubMedCrossRef
22.
Simms CL. Characterization of let-765/nsh-1 and its role in RAS signalling in Caenorhabditis elegans [Doctoral thesis]. British Columbia, Canada: Simon Fraser University; 2009.
23.
Takano A, Zochi R, Hibi M, Terashima T, Katsuyama Y. Function of strawberry notch family genes in the zebrafish brain development. Kobe J Med Sci. 2011;56(5):E220–30.PubMed
24.
Watanabe Y, Miyasaka KY, Kubo A, Kida YS, Nakagawa O, Hirate Y, et al. Notch and Hippo signaling converge on Strawberry Notch 1 (Sbno1) to synergistically activate Cdx2 during specification of the trophectoderm. Sci Rep. 2017;7:46135.PubMedPubMedCentralCrossRef
25.
Maruyama K, Uematsu S, Kondo T, Takeuchi O, Martino MM, Kawasaki T, et al. Strawberry notch homologue 2 regulates osteoclast fusion by enhancing the expression of DC-STAMP. J Exp Med. 2013;210(10):1947–60.PubMedPubMedCentralCrossRef
26.
Brzezinka K, Altmann S, Czesnick H, Nicolas P, Gorka M, Benke E, et al. Arabidopsis FORGETTER1 mediates stress-induced chromatin memory through nucleosome remodeling. Elife. 2016;5: e17061.PubMedPubMedCentralCrossRef
27.
Grill M, Syme TE, Noçon AL, Lu AZX, Hancock D, Rose-John S, et al. Strawberry notch homolog 2 is a novel inflammatory response factor predominantly but not exclusively expressed by astrocytes in the central nervous system. Glia. 2015;63(10):1738–52.PubMedPubMedCentralCrossRef
28.
El Kasmi KC, Smith AM, Williams L, Neale G, Panopolous A, Watowich SS, et al. Cutting edge: a transcriptional repressor and corepressor induced by the STAT3-regulated anti-inflammatory signaling pathway. J Immunol. 2007;179(11):7215–9.PubMedCrossRef
29.
Jing H, Dove C, Zhang Y, Price S, Koneti R, Su HC, editors. Novel immunodysregulation disorder caused by loss-of-function mutations in SBNO2. Clinical Immunology Society 2016 Annual Meeting; 2016; Boston, Massachusetts, USA.
30.
Van Den Bossche MJ, Strazisar M, Cammaerts S, Liekens AM, Vandeweyer G, Depreeuw V, et al. Identification of rare copy number variants in high burden schizophrenia families. Am J Med Genet B Neuropsychiatr Genet. 2013;162(3):273–82.CrossRef
31.
Allen M, Zou F, Chai HS, Younkin CS, Crook J, Pankratz VS, et al. Novel late-onset Alzheimer disease loci variants associate with brain gene expression. Neurology. 2012;79(3):221–8.PubMedPubMedCentralCrossRef
32.
33.
Kim CC, Nakamura MC, Hsieh CL. Brain trauma elicits non-canonical macrophage activation states. J Neuroinflamm. 2016;13(1):117.CrossRef
34.
Metten P, Best KL, Cameron AJ, Saultz AB, Zuraw JM, Yu C-H, et al. Observer-rated ataxia: rating scales for assessment of genetic differences in ethanol-induced intoxication in mice. J Appl Physiol. 2004;97(1):360–8.PubMedCrossRef
35.
Jung SR, Ashhurst TM, West PK, Viengkhou B, King NJC, Campbell IL, et al. Contribution of STAT1 to innate and adaptive immunity during type I interferon-mediated lethal virus infection. PLoS Path. 2020;16(4): e1008525.CrossRef
36.
Carter S, Muller M, Manders P, Campbell I. Induction of the genes for Cxcl9 and Cxcl10 is dependent on IFN-gamma but shows differential cellular expression in experimental autoimmune encephalomyelitis and by astrocytes and microglia in vitro. Glia. 2007;55:1728–39.PubMedCrossRef
37.
Fischer M, Goldschmitt J, Peschel C, Brakenhoff JP, Kallen KJ, Wollmer A, et al. I. A bioactive designer cytokine for human hematopoietic progenitor cell expansion. Nat Biotechnol. 1997;15(2):142–5.PubMedCrossRef
38.
Ousman SS, Campbell IL. Regulation of murine interferon regulatory factor (IRF) gene expression in the central nervous system determined by multiprobe RNase protection assay. Methods Mol Med. 2005;116:115–34.PubMed
39.
Hubbell E, Liu W-M, Mei R. Robust estimators for expression analysis. Bioinformatics. 2002;18(12):1585–92.PubMedCrossRef
40.
41.
Finger JH, Smith CM, Hayamizu TF, McCright IJ, Xu J, Law M, et al. The mouse gene expression database (GXD): 2017 update. Nucleic Acids Res. 2016;45(D1):D730–6.PubMedPubMedCentralCrossRef
42.
Mi H, Muruganujan A, Ebert D, Huang, Thomas PD. PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. Nucleic Acids Res. 2018;47(D1):D419–26.PubMedCentralCrossRef
43.
Barnum SR, Jones JL, Müller-Ladner U, Samimi A, Campbell IL. Chronic complement C3 gene expression in the CNS of transgenic mice with astrocyte-targeted interleukin-6 expression. Glia. 1996;18(2):107–17.PubMedCrossRef
44.
Thomas PD, Kejariwal A, Guo N, Mi H, Campbell MJ, Muruganujan A, et al. Applications for protein sequence–function evolution data: mRNA/protein expression analysis and coding SNP scoring tools. Nucleic Acids Res. 2006;34(suppl_2):W645–50.PubMedPubMedCentralCrossRef
45.
Thomas PD, Campbell MJ, Kejariwal A, Mi H, Karlak B, Daverman R, et al. PANTHER: a library of protein families and subfamilies indexed by function. Genome Res. 2003;13(9):2129–41.PubMedPubMedCentralCrossRef
46.
West PK, Viengkhou B, Campbell IL, Hofer MJ. Microglia responses to interleukin-6 and type I interferons in neuroinflammatory disease. Glia. 2019;67(10):1821–41.PubMed
47.
Milner R, Campbell IL. Increased expression of the β4 and α5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-α in the central nervous system. Mol Cell Neurosci. 2006;33(4):429–40.PubMedPubMedCentralCrossRef
48.
Heyser CJ, Masliah E, Samimi A, Campbell IL, Gold LH. Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain. Proc Natl Acad Sci USA. 1997;94(4):1500–5.PubMedPubMedCentralCrossRef
49.
Coyle-Thompson CA, Banerjee U. The strawberry-notch gene functions with notch in common developmental pathways. Development. 1993;119(2):377–95.PubMedCrossRef
50.
Starr R, Willson TA, Viney EM, Murray LJL, Rayner JR, Jenkins BJ, et al. A family of cytokine-inducible inhibitors of signalling. Nature. 1997;387(6636):917–21.PubMedCrossRef
51.
Sommer U, Schmid C, Sobota RM, Lehmann U, Stevenson NJ, Johnston JA, et al. Mechanisms of SOCS3 phosphorylation upon interleukin-6 stimulation: contributions of src- and receptor-tyrosine kinases. J Biol Chem. 2005;280(36):31478–88.PubMedCrossRef
52.
53.
54.
Chung CD, Liao J, Liu B, Rao, Jay P, Berta P, et al. Specific inhibition of STAT3 signal transduction by PIAS3. Science. 1997;278(5344):1803–5.PubMedCrossRef
55.
Liu B, Mink S, Wong KA, Stein N, Getman C, Dempsey PW, et al. PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity. Nat Immunol. 2004;5:891–8.PubMedCrossRef
56.
Ray S, Boldogh I, Brasier AR. STAT3 NH2-terminal acetylation is activated by the hepatic acute-phase response and required for IL-6 induction of angiotensinogen. Gastroenterology. 2005;129(5):1616–32.PubMedCrossRef
57.
Ray S, Lee C, Hou T, Boldogh I, Brasier AR. Requirement of histone deacetylase1 (HDAC1) in signal transducer and activator of transcription 3 (STAT3) nucleocytoplasmic distribution. Nucleic Acids Res. 2008;36(13):4510–20.PubMedPubMedCentralCrossRef
58.
Wang LH, Yang XY, Zhang, Huang J, Hou J, Li J, et al. Transcriptional inactivation of STAT3 by PPARγ suppresses IL-6-responsive multiple myeloma cells. Immunity. 2004;20(2):205–18.PubMedCrossRef
59.
Kino T, Rice KC, Chrousos GP. The PPARδ agonist GW501516 suppresses interleukin-6-mediated hepatocyte acute phase reaction via STAT3 inhibition. Eur J Clin Invest. 2007;37(5):425–33.PubMedCrossRef
60.
Mansouri RM, Bauge E, Staels B, Gervois P. Systemic and distal repercussions of liver-specific peroxisome proliferator-activated receptor-alpha control of the acute-phase response. Endocrinology. 2008;149(6):3215–23.PubMedCrossRef
61.
van der Meer DL, Degenhardt T, Vaisanen S, de Groot PJ, Heinaniemi M, de Vries SC, et al. Profiling of promoter occupancy by PPARalpha in human hepatoma cells via ChIP-chip analysis. Nucleic Acids Res. 2010;38(9):2839–50.PubMedPubMedCentralCrossRef
62.
Wiesauer I, Gaumannmuller C, Steinparzer I, Strobl B, Kovarik P. Promoter occupancy of STAT1 in interferon responses is regulated by processive transcription. Mol Cell Biol. 2015;35(4):716–27.PubMedPubMedCentralCrossRef
63.
Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131(6):1164–78.PubMedCrossRef
64.
Stephan AH, Barres BA, Stevens B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012;35:369–89.PubMedCrossRef
65.
Adelson JD, Sapp RW, Brott BK, Lee H, Miyamichi K, Luo L, et al. Developmental sculpting of intracortical circuits by MHC Class I H2-Db and H2-Kb. Cereb Cortex. 2016;26(4):1453–63.PubMedCrossRef
66.
Cebrian C, Loike JD, Sulzer D. Neuronal MHC-I expression and its implications in synaptic function, axonal regeneration and Parkinson’s and other brain diseases. Front Neuroanat. 2014;8:114.PubMedPubMedCentralCrossRef
67.
Cebrian C, Zucca FA, Mauri P, Steinbeck JA, Studer L, Scherzer CR, et al. MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Commun. 2014;5:3633.PubMedCrossRef
68.
Nardo G, Trolese MC, Bendotti C. Major histocompatibility complex I expression by motor neurons and its implication in amyotrophic lateral sclerosis. Front Neurol. 2016;7:15.CrossRef
69.
Datwani A, McConnell MJ, Kanold PO, Micheva KD, Busse B, Shamloo M, et al. Classical MHCI molecules regulate retinogeniculate refinement and limit ocular dominance plasticity. Neuron. 2009;64(4):463–70.PubMedPubMedCentralCrossRef
70.
71.
Zar J. Biostatistical analysis. 2nd ed. New Jersey: Prentice-Hall; 1984.
Metadata
Title
Strawberry notch homolog 2 regulates the response to interleukin-6 in the central nervous system
Authors
Taylor E. Syme
Magdalena Grill
Emina Hayashida
Barney Viengkhou
Iain L. Campbell
Markus J. Hofer
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-022-02475-1

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