title: Nogo-receptors NgR1 and NgR2 do not mediate regulation of CD4 T helper responses and CNS repair in experimental autoimmune encephalomyelitis.
abstract: Myelin-associated inhibition of axonal regrowth after injury is considered one important factor that contributes to regeneration failure in the adult central nervous system (CNS). Blocking strategies targeting this pathway have been successfully applied in several nerve injury models, including experimental autoimmune encephalomyelitis (EAE), suggesting myelin-associated inhibitors (MAIs) and functionally related molecules as targets to enhance regeneration in multiple sclerosis. NgR1 and NgR2 were identified as interaction partners for the myelin proteins Nogo-A, MAG and OMgp and are probably mediating their growth-inhibitory effects on axons, although the in vivo relevance of this pathway is currently under debate. Recently, alternative functions of MAIs and NgRs in the regulation of immune cell migration and T cell differentiation have been described. Whether and to what extent NgR1 and NgR2 are contributing to Nogo and MAG-related inhibition of neuroregeneration or immunomodulation during EAE is currently unknown. Here we show that genetic deletion of both receptors does not promote functional recovery during EAE and that NgR1 and NgR2-mediated signals play a minor role in the development of CNS inflammation. Induction of EAE in Ngr1/2-double mutant mice resulted in indifferent disease course and tissue damage when compared to WT controls. Further, the development of encephalitogenic CD4(+) Th1 and Th17 responses was unchanged. However, we observed a slightly increased leukocyte infiltration into the CNS in the absence of NgR1 and NgR2, indicating that NgRs might be involved in the regulation of immune cell migration in the CNS. Our study demonstrates the urgent need for a more detailed knowledge on the multifunctional roles of ligands and receptors involved in CNS regeneration failure.
authors.affiliation: Institute for Neuroimmunology and Clinical MS-Research, Hamburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Steinbach
authors.forename: Claire L
authors.initials: CL
authors.lastname: McDonald
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Schweigreiter
authors.forename: Christine
authors.initials: C
authors.lastname: Bandtlow
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism*; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D000070798:Nogo Proteins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D058851:GPI-Linked Proteins; C104739:Mag protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D000070798:Nogo Proteins; C560529:Omg protein, mouse; D011956:Receptors, Cell Surface; C000603201:Rtn4 protein, mouse
references.citation: Immunity. 2001 Aug;15(2):289-302
references.pmid: 11520463
references.citation: Mol Brain. 2008 Oct 15;1:10
references.pmid: 18922173
references.citation: Lancet. 2008 Oct 25;372(9648):1502-17
references.pmid: 18970977
references.citation: Exp Neurol. 2009 Jun;217(2):371-7
references.pmid: 19328785
references.citation: J Neurosci. 2005 Jan 26;25(4):808-22
references.pmid: 15673660
references.citation: Nat Rev Neurosci. 2004 Feb;5(2):146-56
references.pmid: 14735117
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10997-1002
references.pmid: 16835300
references.citation: Nature. 2001 Jan 18;409(6818):341-6
references.pmid: 11201742
references.citation: BMC Res Notes. 2011 Jan 14;4:6
references.pmid: 21235733
references.citation: Science. 2002 Aug 16;297(5584):1190-3
references.pmid: 12089450
references.citation: Neurology. 2008 Oct 7;71(15):1142-6
references.pmid: 18753473
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1205-10
references.pmid: 15647357
references.citation: Nat Neurosci. 2004 Jul;7(7):736-44
references.pmid: 15184901
references.citation: Nat Rev Neurosci. 2010 Dec;11(12):799-811
references.pmid: 21045861
references.citation: J Neurosci. 2008 Jan 30;28(5):1262-9
references.pmid: 18234903
references.citation: Brain. 2000 Feb;123 ( Pt 2):308-17
references.pmid: 10648438
references.citation: Blood. 2011 Feb 17;117(7):2284-95
references.pmid: 21183689
references.citation: J Neuroinflammation. 2011 Sep 09;8:113
references.pmid: 21906273
references.citation: J Exp Med. 2010 Nov 22;207(12):2595-607
references.pmid: 20975041
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17511-6
references.pmid: 19805174
references.citation: Nature. 2000 Apr 27;404(6781):995-9
references.pmid: 10801128
references.citation: J Neurosci. 2009 May 13;29(19):6348-52
references.pmid: 19439611
references.citation: Ann Neurol. 2010 Apr;67(4):498-507
references.pmid: 20437585
references.citation: Science. 1999 Jul 9;285(5425):260-3
references.pmid: 10398604
references.citation: Annu Rev Immunol. 2005;23:683-747
references.pmid: 15771584
references.citation: Science. 2009 Oct 9;326(5950):298-301
references.pmid: 19815778
references.citation: Nature. 2002 Jun 27;417(6892):941-4
references.pmid: 12068310
references.citation: Neuron. 2007 Mar 1;53(5):649-62
references.pmid: 17329206
references.citation: J Neurosci. 2009 Sep 16;29(37):11511-22
references.pmid: 19759299
references.citation: PLoS One. 2009;4(4):e5218
references.pmid: 19367338
references.citation: J Neuropathol Exp Neurol. 2005 Feb;64(2):129-38
references.pmid: 15751227
references.citation: Am J Pathol. 2000 Jul;157(1):267-76
references.pmid: 10880396
references.citation: J Immunol. 2004 Dec 1;173(11):6981-92
references.pmid: 15557195
references.citation: Trends Neurosci. 2008 May;31(5):221-6
references.pmid: 18394723
references.citation: Science. 2008 Nov 7;322(5903):967-70
references.pmid: 18988857
references.citation: Mult Scler. 2010 Apr;16(4):406-11
references.pmid: 20215480