title: HMGB1 protein does not mediate the inflammatory response in spontaneous spinal cord regeneration: a hint for CNS regeneration.
abstract: Uncontrolled, excessive inflammation contributes to the secondary tissue damage of traumatic spinal cord, and HMGB1 is highlighted for initiation of a vicious self-propagating inflammatory circle by release from necrotic cells or immune cells. Several regenerative-competent vertebrates have evolved to circumvent the second damages during the spontaneous spinal cord regeneration with an unknown HMGB1 regulatory mechanism. By genomic surveys, we have revealed that two paralogs of HMGB1 are broadly retained from fish in the phylogeny. However, their spatial-temporal expression and effects, as shown in lowest amniote gecko, were tightly controlled in order that limited inflammation was produced in spontaneous regeneration. Two paralogs from gecko HMGB1 (gHMGB1) yielded distinct injury and infectious responses, with gHMGB1b significantly up-regulated in the injured cord. The intracellular gHMGB1b induced less release of inflammatory cytokines than gHMGB1a in macrophages, and the effects could be shifted by exchanging one amino acid in the inflammatory domain. Both intracellular proteins were able to mediate neuronal programmed apoptosis, which has been indicated to produce negligible inflammatory responses. In vivo studies demonstrated that the extracellular proteins could not trigger a cascade of the inflammatory cytokines in the injured spinal cord. Signal transduction analysis found that gHMGB1 proteins could not bind with cell surface receptors TLR2 and TLR4 to activate inflammatory signaling pathway. However, they were able to interact with the receptor for advanced glycation end products to potentiate oligodendrocyte migration by activation of both NFκB and Rac1/Cdc42 signaling. Our results reveal that HMGB1 does not mediate the inflammatory response in spontaneous spinal cord regeneration, but it promotes CNS regeneration.
authors: Key Laboratory of Neuroregeneration, Nantong University, Nantong 226007, China.
authors: Yingying
authors: Y
authors: Dong
authors: Yun
authors: Y
authors: Gu
authors: Youjuan
authors: Y
authors: Huan
authors: Yingjie
authors: Y
authors: Wang
authors: Yan
authors: Y
authors: Liu
authors: Mei
authors: M
authors: Liu
authors: Fei
authors: F
authors: Ding
authors: Xiaosong
authors: X
authors: Gu
authors: Yongjun
authors: Y
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D057809:HEK293 Cells; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008116:Lizards; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009474:Neurons / Q000276:immunology / Q000378:metabolism; D010802:Phylogeny; D020033:Protein Isoforms / Q000145:classification / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D012038:Regeneration / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism*; D058630:Spinal Cord Regeneration / Q000235:genetics / Q000276:immunology / Q000502:physiology*
chemical_list: D018076:DNA, Complementary; D024243:HMGB1 Protein; D020033:Protein Isoforms
keywords: CNS; Evolution; HMGB1; Inflammation; Receptor for Advanced Glycation End Products (RAGE); Regeneration; Toll-like receptors (TLR)
references: Cell Biol Int. 2010 Feb;34(2):153-61
references: 19947933
references: J Biol Chem. 1999 Jul 9;274(28):19919-24
references: 10391939
references: Oncol Rep. 2003 Mar-Apr;10(2):445-8
references: 12579287
references: Cell Tissue Res. 2012 Jul;349(1):201-13
references: 22592625
references: Trends Immunol. 2009 Feb;30(2):91-9
references: 19144568
references: Gene. 2007 Jan 31;387(1-2):133-40
references: 17156942
references: Arthritis Rheum. 2003 Apr;48(4):971-81
references: 12687539
references: Mol Med. 2003 Jan-Feb;9(1-2):37-45
references: 12765338
references: PLoS Genet. 2008 Nov;4(11):e1000278
references: 19043548
references: J Immunol. 2005 Jun 15;174(12):7506-15
references: 15944249
references: Int J Biochem Cell Biol. 2012 Dec;44(12):2288-98
references: 23010346
references: J Biol Chem. 2000 Dec 22;275(51):40096-105
references: 11007787
references: J Neurochem. 2004 May;89(3):776-87
references: 15086533
references: J Exp Med. 2000 Aug 21;192(4):565-70
references: 10952726
references: Mol Biol Evol. 2012 Jan;29(1):303-12
references: 21965344
references: Dev Biol. 2007 Jan 1;301(1):62-9
references: 17150209
references: Science. 1999 Jul 9;285(5425):248-51
references: 10398600
references: J Biol Chem. 1991 Sep 5;266(25):16722-9
references: 1885601
references: Cent Nerv Syst Trauma. 1985 Winter;2(4):299-315
references: 3836014
references: Mol Neurobiol. 2012 Jun;45(3):499-506
references: 22580958
references: J Neurosci. 1999 Oct 1;19(19):8182-98
references: 10493720
references: J Biol Chem. 2004 Feb 27;279(9):7370-7
references: 14660645
references: J Neurotrauma. 2001 Sep;18(9):947-56
references: 11565605
references: Biochim Biophys Acta. 2010 Jan-Feb;1799(1-2):141-8
references: 20123076
references: Gene Expr Patterns. 2011 Jan-Feb;11(1-2):3-11
references: 20804857
references: Nature. 2000 Oct 26;407(6807):963-70
references: 11069169
references: J Neuropathol Exp Neurol. 1996 Mar;55(3):280-9
references: 8786386
references: Nucleic Acids Res. 2012 Nov 1;40(20):10356-65
references: 22917588
references: Nat Rev Neurosci. 2008 Jun;9(6):481-93
references: 18490917
references: Biochim Biophys Acta. 2013 Jan;1833(1):101-9
references: 23103427
references: J Mol Neurosci. 2006;29(1):21-8
references: 16757806
references: Biochemistry. 2004 Mar 16;43(10):2935-40
references: 15005629
references: Cytogenet Genome Res. 2003;101(1):33-8
references: 14571134
references: Nat Med. 1997 Jan;3(1):73-6
references: 8986744
references: Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13766-71
references: 11095740
references: J Exp Med. 2005 Jul 4;202(1):145-56
references: 15998793
references: Curr Opin Genet Dev. 2002 Aug;12(4):393-6
references: 12100882
references: Immunology. 2012 May;136(1):11-20
references: 22242941
references: Brain Res Rev. 2011 Jun 24;67(1-2):73-93
references: 21059372
references: Brain. 2000 Oct;123 ( Pt 10):2005-19
references: 11004118
references: Cytokine Growth Factor Rev. 2006 Jun;17(3):189-201
references: 16513409
references: Digestion. 2002;66(2):79-88
references: 12428066
references: Nature. 2008 Jun 19;453(7198):1064-71
references: 18563158
references: FASEB J. 2007 Dec;21(14):3904-16
references: 17628015
references: Brain. 2006 Dec;129(Pt 12):3249-69
references: 17071951
references: Spine (Phila Pa 1976). 2010 May 15;35(11):1109-15
references: 20195207
references: Nat Rev Immunol. 2005 Apr;5(4):331-42
references: 15803152
references: J Cell Sci. 2000 Feb;113 ( Pt 4):611-20
references: 10652254
references: Appl Microbiol Biotechnol. 2001 Dec;57(5-6):579-92
references: 11778865
references: Heredity (Edinb). 2005 Mar;94(3):280-94
references: 15674378
references: Trends Immunol. 2007 Oct;28(10):429-36
references: 17845865
references: J Neurocytol. 1994 May;23(5):323-32
references: 8089705
references: BMC Dev Biol. 2011 Aug 16;11:50
references: 21846350
references: J Surg Res. 2011 Jul;169(1):85-91
references: 20097369
references: Spinal Cord. 2003 Jul;41(7):369-78
references: 12815368
references: EMBO Rep. 2000 Aug;1(2):109-14
references: 11265747
references: BMC Bioinformatics. 2010 Oct 15;11 Suppl 7:S10
references: 21106117
references: PLoS One. 2011 Mar 28;6(3):e17878
references: 21464923
references: Nat Rev Immunol. 2002 Dec;2(12):965-75
references: 12461569
references: Trends Immunol. 2012 Dec;33(12):633-40
references: 23116548
references: J Neurosci Res. 2008 Aug 15;86(11):2414-22
references: 18438937
references: Nat Immunol. 2007 May;8(5):487-96
references: 17417641
references: Spine (Phila Pa 1976). 2011 Dec 1;36(25):2122-9
references: 21343866
references: Biochim Biophys Acta. 2010 Jan-Feb;1799(1-2):149-56
references: 19948257
references: Nat Rev Neurosci. 2011 Jun 15;12(7):388-99
references: 21673720
references: J Cereb Blood Flow Metab. 2008 May;28(5):927-38
references: 18000511
references: Prog Neurobiol. 2012 Mar;96(3):322-39
references: 22307058
references: Am J Physiol Cell Physiol. 2006 Mar;290(3):C917-24
references: 16267105
references: Curr Top Microbiol Immunol. 2009;336:121-36
references: 19688331
references: Mol Cell Biol. 1999 Aug;19(8):5237-46
references: 10409715
references: J Biol Chem. 1995 Oct 27;270(43):25752-61
references: 7592757
references: Am J Hum Genet. 1998 Dec;63(6):1573-7
references: 9837808
references: Science. 2009 Mar 27;323(5922):1722-5
references: 19264983
references: Immunology. 1997 Oct;92(2):252-8
references: 9415034
references: J Biol Chem. 1987 Dec 5;262(34):16625-35
references: 3680268
references: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references: 9254694
references: Eur J Immunol. 2004 Jun;34(6):1503-12
references: 15162419
references: EMBO J. 2007 Feb 21;26(4):1129-39
references: 17268551
references: J Neurosci. 2008 Oct 29;28(44):11391-400
references: 18971481
references: Trends Immunol. 2008 Aug;29(8):357-65
references: 18599350
references: Nucleic Acids Res. 1993 Jul 25;21(15):3427-36
references: 8346022
references: J Immunol. 2000 Sep 15;165(6):2950-4
references: 10975801
references: Nature. 2002 Jul 11;418(6894):191-5
references: 12110890
references: Immunol Rev. 2007 Dec;220:35-46
references: 17979838
references: Scand J Immunol. 2005 Jan;61(1):1-9
references: 15644117
references: Dev Dyn. 2003 Feb;226(2):245-56
references: 12557203
references: Curr Mol Med. 2007 Dec;7(8):725-34
references: 18331230
references: Trends Pharmacol Sci. 2004 Aug;25(8):407-12
references: 15276709
references: Spine (Phila Pa 1976). 2000 Jul 15;25(14):1859-66
references: 10888960
references: J Exp Med. 2005 Apr 4;201(7):1135-43
references: 15795240
references: Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11942-7
references: 20547845
references: Syst Biol. 2010 May;59(3):307-21
references: 20525638
references: Clin Chim Acta. 2007 Jan;375(1-2):36-42
references: 16979611
references: J Cell Biochem. 2012 Jun;113(6):1842-51
references: 22234988
references: J Neurosci. 2006 Jun 14;26(24):6413-21
references: 16775128