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Journal of Neuroinflammation

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Open Access 01-12-2017 | Research

Receptor tyrosine kinases play a significant role in human oligodendrocyte inflammation and cell death associated with the Lyme disease bacterium Borrelia burgdorferi

Authors: Geetha Parthasarathy, Mario T. Philipp

Published in: Journal of Neuroinflammation | Issue 1/2017

Abstract

Background

In previous studies, human oligodendrocytes were demonstrated to undergo apoptosis in the presence of Borrelia burgdorferi under an inflammatory milieu. Subsequently, we determined that the MEK/ERK pathway played a significant role in triggering downstream inflammation as well as apoptosis. However, the identity of receptors triggered by exposure to B. burgdorferi and initiating signaling events was unknown.

Methods

In this study, we explored the role of several TLR and EGFR/FGFR/PDGFR tyrosine kinase pathways in inducing inflammation in the presence of B. burgdorferi, using siRNA and/or inhibitors, in MO3.13 human oligodendrocytes. Cell death and apoptosis assays were also carried out in the presence or absence of specific receptor inhibitors along with the bacteria to determine the role of these receptors in apoptosis induction. The expression pattern of specific receptors with or without B. burgdorferi was also determined.

Results

TLRs 2 and 5 had a minimal role in inducing inflammation, particularly IL-6 production. Rather, their effect was mostly inhibitory, with TLR2 downregulation significantly upregulating CXCL8, and CXCL (1,2,3) levels, and TLR5 likely having a similar role in CXCL8, CXCL(1,2,3), and CCL5 levels. TLR4 contributed mostly towards CCL5 production. On the other hand, inhibition of all three EGF/FGF/PDGF receptors significantly downregulated all five of the inflammatory mediators tested even in the presence of B. burgdorferi. Their inhibition also downregulated overall cell death and apoptosis levels. The expression pattern of these receptors, as assessed by immunohistochemistry indicated that the PDGFRβ receptor was the most predominantly expressed receptor, followed by FGFR, although no significant differences were discernible between presence and absence of bacteria. Interestingly, inhibition of individual EGFR, FGFR, or PDGFR receptors did not indicate an individual role for any of these receptors in the overall downregulation of pathogenesis. Contrarily, suppression of FGFR signaling alone in the presence of bacteria significantly upregulated inflammatory mediator levels indicating that it might control an inhibitory pathway when triggered individually.

Conclusions

Unlike TLRs, EGF/FGF/PDGF receptors collectively play a significant role in the inflammation and apoptosis of human oligodendrocytes as mediated by B. burgdorferi. It is likely that these three receptors need to be triggered simultaneously to achieve this effect.

Koedel U, Fingerle V, Pfister HW. Lyme neuroborreliosis-epidemiology, diagnosis and management. Nat Rev Neurol. 2015;11:446–56.CrossRefPubMed

Ramesh G, Borda JT, Gill A, Ribka EP, Morici LA, Mottram P, Martin DS, Jacobs MB, Didier PJ, Philipp MT. Possible role of glial cells in the onset and progression of Lyme neuroborreliosis. J Neuroinflammation. 2009;6:23.CrossRefPubMedPubMedCentral

Ramesh G, Borda JT, Dufour J, Kaushal D, Ramamoorthy R, Lackner AA, Philipp MT. Interaction of the Lyme disease spirochete Borrelia burgdorferi with brain parenchyma elicits inflammatory mediators from glial cells as well as glial and neuronal apoptosis. Am J Pathol. 2008;173:1415–27.CrossRefPubMedPubMedCentral

Ramesh G, Didier PJ, England JD, Santana-Gould L, Doyle-Meyers LA, Martin DS, Jacobs MB, Philipp MT. Inflammation in the pathogenesis of Lyme neuroborreliosis. Am J Pathol. 2015;185:1344–60.CrossRefPubMedPubMedCentral

Myers TA, Kaushal D, Philipp MT. Microglia are mediators of Borrelia burgdorferi-induced apoptosis in SH-SY5Y neuronal cells. PLoS Pathog. 2009;5:e1000659.CrossRefPubMedPubMedCentral

Ramesh G, Benge S, Pahar B, Philipp MT. A possible role for inflammation in mediating apoptosis of oligodendrocytes as induced by the Lyme disease spirochete Borrelia burgdorferi. J Neuroinflammation. 2012;9:72.PubMedPubMedCentral

Parthasarathy G, Philipp MT. The MEK/ERK pathway is the primary conduit for Borrelia burgdorferi-induced inflammation and P53-mediated apoptosis in oligodendrocytes. Apoptosis. 2014;19:76–89.CrossRefPubMedPubMedCentral

Purser JE, Norris SJ. Correlation between plasmid content and infectivity in Borrelia burgdorferi. Proc Natl Acad Sci U S A. 2000;97:13865–70.CrossRefPubMedPubMedCentral

Bernardino AL, Myers TA, Alvarez X, Hasegawa A, Philipp MT. Toll-like receptors: insights into their possible role in the pathogenesis of Lyme neuroborreliosis. Infect Immun. 2008;76:4385–95.CrossRefPubMedPubMedCentral

10.

Parthasarathy G, Philipp MT. Inflammatory mediator release from primary rhesus microglia in response to Borrelia burgdorferi results from the activation of several receptors and pathways. J Neuroinflammation. 2015;12:60.CrossRefPubMedPubMedCentral

11.

Qu WS, Tian DS, Guo ZB, Fang J, Zhang Q, Yu ZY, Xie MJ, Zhang HQ, Lu JG, Wang W. Inhibition of EGFR/MAPK signaling reduces microglial inflammatory response and the associated secondary damage in rats after spinal cord injury. J Neuroinflammation. 2012;9:178.CrossRefPubMedPubMedCentral

12.

Bethel-Brown C, Yao H, Hu G, Buch S. Platelet-derived growth factor (PDGF)-BB-mediated induction of monocyte chemoattractant protein 1 in human astrocytes: implications for HIV-associated neuroinflammation. J Neuroinflammation. 2012;9:262.CrossRefPubMedPubMedCentral

13.

Crespo O, Kang SC, Daneman R, Lindstrom TM, Ho PP, Sobel RA, Steinman L, Robinson WH. Tyrosine kinase inhibitors ameliorate autoimmune encephalomyelitis in a mouse model of multiple sclerosis. J Clin Immunol. 2011;31:1010–20.CrossRefPubMedPubMedCentral

14.

Hsieh HL, Yang CM. Role of redox signaling in neuroinflammation and neurodegenerative diseases. Biomed Res Int. 2013;2013:484613.PubMedPubMedCentral

15.

Rahman S, Shering M, Ogden NH, Lindsay R, Badawi A. Toll-like receptor cascade and gene polymorphism in host-pathogen interaction in Lyme disease. J Inflamm Res. 2016;9:91–102.PubMedPubMedCentral

16.

Shin OS, Isberg RR, Akira S, Uematsu S, Behera AK, Hu LT. Distinct roles for MyD88 and Toll-like receptors 2, 5, and 9 in phagocytosis of Borrelia burgdorferi and cytokine induction. Infect Immun. 2008;76:2341–51.CrossRefPubMedPubMedCentral

17.

Yang XP, Fu JY, Yang RC, Liu WT, Zhang T, Yang B, Miao L, Dou BB, Tan C, Chen HC, Wang XR. EGFR transactivation contributes to neuroinflammation in Streptococcus suis meningitis. J Neuroinflammation. 2016;13:274.CrossRefPubMedPubMedCentral

18.

Pathak P, Kumar A, Jha P, Purkait S, Faruq M, Suri A, Suri V, Sharma MC, Sarkar C. Genetic alterations related to BRAF-FGFR genes and dysregulated MAPK/ERK/mTOR signaling in adult pilocytic astrocytoma. Brain Pathol. 2017. doi:10.1111/bpa.12444.

19.

Huang C, Yuan P, Wu J, Huang J. Estrogen regulates excitatory amino acid carrier 1 (EAAC1) expression through sphingosine kinase 1 (SphK1) transacting FGFR-mediated ERK signaling in rat C6 astroglial cells. Neuroscience. 2016;319:9–22.CrossRefPubMed

20.

Zhang H, Sun JD, Yan LJ, Zhao XP. PDGF-D/PDGFRbeta promotes tongue squamous carcinoma cell (TSCC) progression via activating p38/AKT/ERK/EMT signal pathway. Biochem Biophys Res Commun. 2016;478:845–51.CrossRefPubMed

21.

Abe Y, Namba H, Zheng Y, Nawa H. In situ hybridization reveals developmental regulation of ErbB1-4 mRNA expression in mouse midbrain: implication of ErbB receptors for dopaminergic neurons. Neuroscience. 2009;161:95–110.CrossRefPubMed

22.

Grinspan J, Wrabetz L, Kamholz J. Oligodendrocyte maturation and myelin gene expression in PDGF-treated cultures from rat cerebral white matter. J Neurocytol. 1993;22:322–33.CrossRefPubMed

23.

Baumann N, Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev. 2001;81:871–927.PubMed

24.

Furusho M, Kaga Y, Ishii A, Hebert JM, Bansal R. Fibroblast growth factor signaling is required for the generation of oligodendrocyte progenitors from the embryonic forebrain. J Neurosci. 2011;31:5055–66.CrossRefPubMedPubMedCentral

25.

Oh LY, Denninger A, Colvin JS, Vyas A, Tole S, Ornitz DM, Bansal R. Fibroblast growth factor receptor 3 signaling regulates the onset of oligodendrocyte terminal differentiation. J Neurosci. 2003;23:883–94.PubMed

26.

Bansal R, Kumar M, Murray K, Morrison RS, Pfeiffer SE. Regulation of FGF receptors in the oligodendrocyte lineage. Mol Cell Neurosci. 1996;7:263–75.CrossRefPubMed

27.

Zammit C, Barnard R, Gomm J, Coope R, Shousha S, Coombes C, Johnston C. Altered intracellular localization of fibroblast growth factor receptor 3 in human breast cancer. J Pathol. 2001;194:27–34.CrossRefPubMed

28.

Johnston CL, Cox HC, Gomm JJ, Coombes RC. Fibroblast growth factor receptors (FGFRs) localize in different cellular compartments. A splice variant of FGFR-3 localizes to the nucleus. J Biol Chem. 1995;270:30643–50.CrossRefPubMed

29.

Stachowiak EK, Maher PA, Tucholski J, Mordechai E, Joy A, Moffett J, Coons S, Stachowiak MK. Nuclear accumulation of fibroblast growth factor receptors in human glial cells—association with cell proliferation. Oncogene. 1997;14:2201–11.CrossRefPubMed

30.

Prudovsky I, Savion N, Zhan X, Friesel R, Xu J, Hou J, McKeehan WL, Maciag T. Intact and functional fibroblast growth factor (FGF) receptor-1 trafficks near the nucleus in response to FGF-1. J Biol Chem. 1994;269:31720–4.PubMed

31.

Bromann PA, Korkaya H, Courtneidge SA. The interplay between Src family kinases and receptor tyrosine kinases. Oncogene. 2004;23:7957–68.CrossRefPubMed

32.

Christofori G. Split personalities: the agonistic antagonist Sprouty. Nat Cell Biol. 2003;5:377–9.CrossRefPubMed

33.

Cattaneo F, Guerra G, Parisi M, De Marinis M, Tafuri D, Cinelli M, Ammendola R. Cell-surface receptors transactivation mediated by G protein-coupled receptors. Int J Mol Sci. 2014;15:19700–28.CrossRefPubMedPubMedCentral

34.

Shah BH, Catt KJ. GPCR-mediated transactivation of RTKs in the CNS: mechanisms and consequences. Trends Neurosci. 2004;27:48–53.CrossRefPubMed

35.

Roggiani F, Mezzanzanica D, Rea K, Tomassetti A. Guidance of signaling activations by cadherins and integrins in epithelial ovarian cancer cells. Int J Mol Sci. 2016;17(9). doi:10.3390/ijms17091387.

36.

Arias-Salgado EG, Lizano S, Sarkar S, Brugge JS, Ginsberg MH, Shattil SJ. Src kinase activation by direct interaction with the integrin beta cytoplasmic domain. Proc Natl Acad Sci U S A. 2003;100:13298–302.CrossRefPubMedPubMedCentral

37.

Petnicki-Ocwieja T, Kern A. Mechanisms of Borrelia burgdorferi internalization and intracellular innate immune signaling. Front Cell Infect Microbiol. 2014;4:175.CrossRefPubMedPubMedCentral

38.

Ji TH, Grossmann M, Ji I. G protein-coupled receptors. I. Diversity of receptor-ligand interactions. J Biol Chem. 1998;273:17299–302.CrossRefPubMed

39.

Goldstein M, Meller I, Orr-Urtreger A. FGFR1 over-expression in primary rhabdomyosarcoma tumors is associated with hypomethylation of a 5’ CpG island and abnormal expression of the AKT1, NOG, and BMP4 genes. Genes Chromosomes Cancer. 2007;46:1028–38.CrossRefPubMed

Title: Receptor tyrosine kinases play a significant role in human oligodendrocyte inflammation and cell death associated with the Lyme disease bacterium Borrelia burgdorferi
Authors: Geetha Parthasarathy
Mario T. Philipp
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-017-0883-9

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Receptor tyrosine kinases play a significant role in human oligodendrocyte inflammation and cell death associated with the Lyme disease bacterium Borrelia burgdorferi

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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