Abstract
Numerous NG2 cells, also called oligodendrocyte progenitor cells (OPCs), exist ubiquitously in the gray and white matter in the adult central nervous system (CNS). Although NG2 cells could become active by upregulation of NG2 expression and hypertrophy or extension of their processes under various neuropathological conditions, their actual role in the brain remains to be illustrated. In view of the fact that the synergy of cytokine and chemokine networks plays an important role in CNS inflammation and immunity, we have assumed that the NG2 cells might take part in brain inflammation and immunity by making a contribution to the pool of cytokines or chemokines. In the current study, NG2-expressing OPCs were prepared from cerebral hemispheres of postnatal day 0 or 1 Sprague–Dawley rats. Our results showed that NG2-expressing OPCs, verified by immunohistological staining of anti-NG2 antibody and anti-platelet-derived growth factor receptor alpha (PDGFRα) antibody, presented binding affinity to lipopolysaccharide (LPS), a commonly used stimulator in a neuroinflammatory model. Using cytokine antibody array, QPCR and ELISA, we have further shown that LPS could upregulate the expression of cytokine induced neutrophil chemoattractant-3 (CINC-3) and LPS induced CXC chemokine (LIX) in primary NG2-expressing OPCs, without the alteration in cell number of NG2-expressing OPCs. In addition, the cells bearing the receptor for these two cytokines included microglia and OPCs. Taken together, our results suggest that NG2-expressing OPCs could response to LPS and may take part in neuroinflammatory process, through secreting cytokines and chemokines to exert an effect on target cells (OPCs and microglia).
Similar content being viewed by others
References
Dawson MR, Polito A, Levine JM, Reynolds R (2003) NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS. Mol Cell Neurosci 24:476–488
Dawson MR, Levine JM, Reynolds R (2000) NG2-expressing cells in the central nervous system: Are they oligodendroglial progenitors? J Neurosci Res 61:471–479
Chang A, Nishiyama A, Peterson J, Prineas J, Trapp BD (2000) NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J Neurosci 20:6404–6412
Nishiyama A, Komitova M, Suzuki R, Zhu X (2009) Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nat Rev Neurosci 10:9–22
Hill RA, Nishiyama A (2014) NG2 cells (polydendrocytes): listeners to the neural network with diverse properties. Glia 62:1195–1210
Nishiyama A, Lin XH, Giese N, Heldin CH, Stallcup WB (1996) Co-localization of NG2 proteoglycan and PDGF alpha-receptor on O2A progenitor cells in the developing rat brain. J Neurosci Res 43:299–314
Nishiyama A, Chang A, Trapp BD (1999) NG2+ glial cells: a novel glial cell population in the adult brain. J Neuropathol Exp Neurol 58:1113–1124
Nishiyama A (2007) Polydendrocytes: NG2 cells with many roles in development and repair of the CNS. Neuroscientist 13:62–76
Zhu X, Hill RA, Nishiyama A (2008) NG2 cells generate oligodendrocytes and gray matter astrocytes in the spinal cord. Neuron Glia Biol 4:19–26
Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, Kessaris N, Richardson WD (2008) PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 11:1392–1401
Kang SH, Fukaya M, Yang JK, Rothstein JD, Bergles DE (2010) NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68:668–681
Huang W, Zhao N, Bai X, Karram K, Trotter J, Goebbels S, Scheller A, Kirchhoff F (2014) Novel NG2-CreERT2 knock-in mice demonstrate heterogeneous differentiation potential of NG2 glia during development. Glia 62:896–913
Hill RA, Patel KD, Goncalves CM, Grutzendler J, Nishiyama A (2014) Modulation of oligodendrocyte generation during a critical temporal window after NG2 cell division. Nat Neurosci 17:1518–1527
Watanabe M, Toyama Y, Nishiyama A (2002) Differentiation of proliferated NG2-positive glial progenitor cells in a remyelinating lesion. J Neurosci Res 69:826–836
Reynolds R, Dawson M, Papadopoulos D, Polito A, Di Bello IC, Pham-Dinh D, Levine J (2002) The response of NG2-expressing oligodendrocyte progenitors to demyelination in MOG-EAE and MS. J Neurocytol 31:523–536
Polito A, Reynolds R (2005) NG2-expressing cells as oligodendrocyte progenitors in the normal and demyelinated adult central nervous system. J Anat 207:707–716
Bu J, Banki A, Wu Q, Nishiyama A (2004) Increased NG2(+) glial cell proliferation and oligodendrocyte generation in the hypomyelinating mutant shiverer. Glia 48:51–63
Belachew S, Chittajallu R, Aguirre AA, Yuan X, Kirby M, Anderson S, Gallo V (2003) Postnatal NG2 proteoglycan-expressing progenitor cells are intrinsically multipotent and generate functional neurons. J Cell Biol 161:169–186
Aguirre AA, Chittajallu R, Belachew S, Gallo V (2004) NG2-expressing cells in the subventricular zone are type C-like cells and contribute to interneuron generation in the postnatal hippocampus. J Cell Biol 165:575–589
Aguirre A, Gallo V (2004) Postnatal neurogenesis and gliogenesis in the olfactory bulb from NG2-expressing progenitors of the subventricular zone. J Neurosci 24:10530–10541
Tsoa RW, Coskun V, Ho CK, de Vellis J, Sun YE (2014) Spatiotemporally different origins of NG2 progenitors produce cortical interneurons versus glia in the mammalian forebrain. Proc Natl Acad Sci USA 111:7444–7449
Robins SC, Trudel E, Rotondi O, Liu X, Djogo T, Kryzskaya D, Bourque CW, Kokoeva MV (2013) Evidence for NG2-glia derived, adult-born functional neurons in the hypothalamus. PLoS One 8:e78236
Leoni G, Rattray M, Butt AM (2009) NG2 cells differentiate into astrocytes in cerebellar slices. Mol Cell Neurosci 42:208–218
Sakry D, Karram K, Trotter J (2011) Synapses between NG2 glia and neurons. J Anat 219:2–7
Levine JM (1994) Increased expression of the NG2 chondroitin-sulfate proteoglycan after brain injury. J Neurosci 14:4716–4730
Rhodes KE, Raivich G, Fawcett JW (2006) The injury response of oligodendrocyte precursor cells is induced by platelets, macrophages and inflammation-associated cytokines. Neuroscience 140:87–100
Ong WY, Levine JM (1999) A light and electron microscopic study of NG2 chondroitin sulfate proteoglycan-positive oligodendrocyte precursor cells in the normal and kainate-lesioned rat hippocampus. Neuroscience 92:83–95
Levine JM, Reynolds R (1999) Activation and proliferation of endogenous oligodendrocyte precursor cells during ethidium bromide-induced demyelination. Exp Neurol 160:333–347
Sahinkaya FR, Milich LM, McTigue DM (2014) Changes in NG2 cells and oligodendrocytes in a new model of intraspinal hemorrhage. Exp Neurol 255:113–126
Taylor DL, Pirianov G, Holland S, McGinnity CJ, Norman AL, Reali C, Diemel LT, Gveric D, Yeung D, Mehmet H (2010) Attenuation of proliferation in oligodendrocyte precursor cells by activated microglia. J Neurosci Res 88:1632–1644
Okamura RM, Lebkowski J, Au M, Priest CA, Denham J, Majumdar AS (2007) Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells. J Neuroimmunol 192:134–144
Kang Z, Wang C, Zepp J, Wu L, Sun K, Zhao J, Chandrasekharan U, DiCorleto PE, Trapp BD, Ransohoff RM, Li X (2013) Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells. Nat Neurosci 16:1401–1408
Sypecka J, Sarnowska A (2014) The neuroprotective effect exerted by oligodendroglial progenitors on ischemically impaired hippocampal cells. Mol Neurobiol 49:685–701
Beutler B (2000) Tlr4: central component of the sole mammalian LPS sensor. Curr Opin Immunol 12:20–26
Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801
Zhu L, Xiang P, Guo K, Wang A, Lu J, Tay SS, Jiang H, He BP (2012) Microglia/monocytes with NG2 expression have no phagocytic function in the cortex after LPS focal injection into the rat brain. Glia 60:1417–1426
Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, Jensen FE, Rosenberg PA, Volpe JJ, Vartanian T (2002) The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 22:2478–2486
Pang Y, Cai Z, Rhodes PG (2003) Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide. Brain Res Dev Brain Res 140:205–214
Paintlia MK, Paintlia AS, Barbosa E, Singh I, Singh AK (2004) N-acetylcysteine prevents endotoxin-induced degeneration of oligodendrocyte progenitors and hypomyelination in developing rat brain. J Neurosci Res 78:347–361
Wennstrom M, Janelidze S, Bay-Richter C, Minthon L, Brundin L (2014) Pro-inflammatory cytokines reduce the proliferation of NG2 cells and increase shedding of NG2 in vivo and in vitro. PLoS One 9:e109387
Filipovic R, Zecevic N (2005) Lipopolysaccharide affects Golli expression and promotes proliferation of oligodendrocyte progenitors. Glia 49:457–466
Pang Y, Campbell L, Zheng B, Fan L, Cai Z, Rhodes P (2010) Lipopolysaccharide-activated microglia induce death of oligodendrocyte progenitor cells and impede their development. Neuroscience 166:464–475
Pang Y, Cai Z, Rhodes PG (2000) Effects of lipopolysaccharide on oligodendrocyte progenitor cells are mediated by astrocytes and microglia. J Neurosci Res 62:510–520
Li J, Ramenaden ER, Peng J, Koito H, Volpe JJ, Rosenberg PA (2008) Tumor necrosis factor alpha mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are present. J Neurosci 28:5321–5330
Veenstra M, Ransohoff RM (2012) Chemokine receptor CXCR2: Physiology regulator and neuroinflammation controller? J Neuroimmunol 246:1–9
Omari KM, John GR, Sealfon SC, Raine CS (2005) CXC chemokine receptors on human oligodendrocytes: implications for multiple sclerosis. Brain 128:1003–1015
Nguyen D, Stangel M (2001) Expression of the chemokine receptors CXCR1 and CXCR2 in rat oligodendroglial cells. Brain Res Dev Brain Res 128:77–81
Filipovic R, Jakovcevski I, Zecevic N (2003) GRO-alpha and CXCR2 in the human fetal brain and multiple sclerosis lesions. Dev Neurosci 25:279–290
Zhang Y, Chen KN, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng SY, Liddelow SA, Zhang CL, Daneman R, Maniatis T, Barres BA, Wu JQ (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947
Wu Q, Miller RH, Ransohoff RM, Robinson S, Bu J, Nishiyama A (2000) Elevated levels of the chemokine GRO-1 correlate with elevated oligodendrocyte progenitor proliferation in the jimpy mutant. J Neurosci 20:2609–2617
Tsai HH, Frost E, To V, Robinson S, Ffrench-Constant C, Geertman R, Ransohoff RM, Miller RH (2002) The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. Cell 110:373–383
Tirotta E, Ransohoff RM, Lane TE (2011) CXCR2 signaling protects oligodendrocyte progenitor cells from IFN-gamma/CXCL10-mediated apoptosis. Glia 59:1518–1528
Tirotta E, Kirby LA, Hatch MN, Lane TE (2012) IFN-gamma-induced apoptosis of human embryonic stem cell derived oligodendrocyte progenitor cells is restricted by CXCR2 signaling. Stem cell Res 9:208–217
Robinson S, Tani M, Strieter RM, Ransohoff RM, Miller RH (1998) The chemokine growth-regulated oncogene-alpha promotes spinal cord oligodendrocyte precursor proliferation. J Neurosci 18:10457–10463
Robinson S, Franic LA (2001) Chemokine GRO1 and the spatial and temporal regulation of oligodendrocyte precursor proliferation. Dev Neurosci 23:338–345
Vora P, Pillai P, Mustapha J, Kowal C, Shaffer S, Bose R, Namaka M, Frost EE (2012) CXCL1 regulation of oligodendrocyte progenitor cell migration is independent of calcium signaling. Exp Neurol 236:259–267
Ambrosini E, Aloisi F (2004) Chemokines and glial cells: a complex network in the central nervous system. Neurochem Res 29:1017–1038
Ubogu EE, Cossoy MB, Ransohoff RM (2006) The expression and function of chemokines involved in CNS inflammation. Trends Pharmacol Sci 27:48–55
Acknowledgments
This study was supported by National Medical Research Council of Singapore (NMRC/EDG/0036/2008) and National Research Foundation of Singapore (NRF-CRP 002-082).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Li, Y., Du, Xl. & He, Bp. Lipopolysaccharide Upregulates the Expression of CINC-3 and LIX in Primary NG2 Cells. Neurochem Res 41, 1448–1457 (2016). https://doi.org/10.1007/s11064-016-1856-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-016-1856-6