title: Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury.
abstract: A key component in the response of the nervous system to injury is the proliferation and switch to a "proinflammatory" phenotype by microglia (microgliosis). In situations where the blood-brain barrier is intact, microglial numbers increase via the proliferation and chemotaxis of resident microglia; however, there is limited knowledge regarding the factors mediating this response. After peripheral nerve injury, a dorsal horn microgliosis develops, which directly contributes to the development of neuropathic pain. Neuregulin-1 (NRG-1) is a growth and differentiation factor with a well characterized role in neural and cardiac development. Microglia express the NRG1 receptors erbB2, 3, and 4, and NRG1 signaling via the erbB2 receptor stimulated microglial proliferation, chemotaxis, and survival, as well as interleukin-1beta release in vitro. Intrathecal treatment with NRG1 resulted in microglial proliferation within the dorsal horn, and these cells developed an activated morphology. This microglial response was associated with the development of both mechanical and cold pain-related hypersensitivity. Primary afferents express NRG1, and after spinal nerve ligation (SNL) we observed both an increase in NRG1 within the dorsal horn as well as activation of erbB2 specifically within microglia. Blockade of the erbB2 receptor or sequestration of endogenous NRG after SNL reduced the proliferation, the number of microglia with an activated morphology, and the expression of phospho-P38 by microglia. Furthermore, consequent to such changes, the mechanical pain-related hypersensitivity and cold allodynia were reduced. NRG1-erbB signaling therefore represents a novel pathway regulating the injury response of microglia.
authors.affiliation: Wolfson Center for Age Related Diseases, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Margarita
authors.initials: M
authors.lastname: Calvo
authors.forename: Ning
authors.initials: N
authors.lastname: Zhu
authors.forename: Christoforos
authors.initials: C
authors.lastname: Tsantoulas
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Ma
authors.forename: John
authors.initials: J
authors.lastname: Grist
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Loeb
authors.forename: David L H
authors.initials: DL
authors.lastname: Bennett
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology; D005911:Gliosis / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D017628:Microglia / Q000502:physiology*; D020890:Neuregulin-1 / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000503:physiopathology*; D020671:Posterior Horn Cells / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013127:Spinal Nerves / Q000293:injuries*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C490580:Nrg1 protein, rat
references.citation: J Neurosci. 2007 May 30;27(22):5837-44
references.pmid: 17537952
references.citation: Nature. 2003 Aug 14;424(6950):778-83
references.pmid: 12917686
references.citation: Mol Cell Neurosci. 1997;10(3-4):184-95
references.pmid: 9532580
references.citation: Nat Neurosci. 2007 Dec;10(12):1538-43
references.pmid: 18026097
references.citation: Int J Oncol. 2000 Oct;17(4):629-41
references.pmid: 10995872
references.citation: EMBO J. 1997 Apr 1;16(7):1647-55
references.pmid: 9130710
references.citation: Glia. 2001 Mar 1;33(3):256-66
references.pmid: 11241743
references.citation: Nat Neurosci. 2007 Nov;10(11):1361-8
references.pmid: 17965656
references.citation: J Neurosci Res. 1997 Dec 1;50(5):673-83
references.pmid: 9418956
references.citation: Nat Rev Neurosci. 2008 Jun;9(6):437-52
references.pmid: 18478032
references.citation: Jpn J Pharmacol. 2000 Aug;83(4):351-4
references.pmid: 11001183
references.citation: Pain. 1992 Sep;50(3):355-363
references.pmid: 1333581
references.citation: Anesthesiology. 2006 Jul;105(1):146-53
references.pmid: 16810006
references.citation: Brain Res. 2009 Mar 3;1258:1-11
references.pmid: 19150438
references.citation: Neuron. 2001 May;30(2):399-410
references.pmid: 11395002
references.citation: Nat Neurosci. 2003 Nov;6(11):1186-93
references.pmid: 14555954
references.citation: J Neurosci. 2007 Nov 28;27(48):13065-73
references.pmid: 18045900
references.citation: J Neurosci Res. 1990 Sep;27(1):36-42
references.pmid: 2254955
references.citation: J Neurosci. 1986 Aug;6(8):2163-78
references.pmid: 3018187
references.citation: J Pathol. 2002 Dec;198(4):523-33
references.pmid: 12434423
references.citation: Nat Neurosci. 2007 Nov;10(11):1387-94
references.pmid: 17965659
references.citation: J Cell Biol. 1995 Jul;130(1):127-35
references.pmid: 7540614
references.citation: Exp Neurol. 1999 Jun;157(2):289-304
references.pmid: 10364441
references.citation: Nat Neurosci. 2007 Dec;10(12):1544-53
references.pmid: 18026096
references.citation: J Neurosci. 2003 May 15;23(10):4017-22
references.pmid: 12764087
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8514-9
references.pmid: 12824464
references.citation: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references.pmid: 11252954
references.citation: Annu Rev Immunol. 2009;27:119-45
references.pmid: 19302036
references.citation: Curr Opin Neurobiol. 2006 Oct;16(5):492-500
references.pmid: 16962312
references.citation: J Neurosci. 2001 Mar 15;21(6):1975-82
references.pmid: 11245682
references.citation: J Neurosci. 1997 Nov 1;17(21):8476-90
references.pmid: 9334420
references.citation: J Neurochem. 2004 Oct;91(1):176-88
references.pmid: 15379898
references.citation: Eur J Pain. 2009 Mar;13(3):263-72
references.pmid: 18554968
references.citation: J Neurosci. 2008 Mar 12;28(11):2892-902
references.pmid: 18337420
references.citation: J Neurosci. 2009 Jun 17;29(24):7667-78
references.pmid: 19535578
references.citation: Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1064-8
references.pmid: 8302832
references.citation: EMBO J. 2002 Feb 1;21(3):202-10
references.pmid: 11823413
references.citation: J Neurosci. 2008 May 14;28(20):5189-94
references.pmid: 18480275
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9773-8
references.pmid: 16785428
references.citation: Pain. 2008 Mar;135(1-2):37-47
references.pmid: 17560721
references.citation: J Neurosci. 1988 Dec;8(12):4707-17
references.pmid: 3058881
references.citation: Neuron. 2005 Sep 1;47(5):681-94
references.pmid: 16129398
references.citation: J Neuroimmunol. 2003 Mar;136(1-2):67-74
references.pmid: 12620644
references.citation: Nature. 1995 Nov 23;378(6555):394-8
references.pmid: 7477377
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10655-60
references.pmid: 17551020
references.citation: Cell. 1994 Jul 15;78(1):5-8
references.pmid: 8033211
references.citation: J Biol Chem. 2009 Nov 13;284(46):32108-15
references.pmid: 19717564
references.citation: J Neurosci. 2005 Mar 30;25(13):3478-87
references.pmid: 15800203
references.citation: J Immunol. 2001 Feb 15;166(4):2717-26
references.pmid: 11160337
references.citation: J Neurosci. 2004 Jul 7;24(27):6218-27
references.pmid: 15240814
references.citation: Nat Med. 1995 Jul;1(7):644-8
references.pmid: 7585144
references.citation: Exp Mol Pathol. 1999 Sep;67(1):15-25
references.pmid: 10493889
references.citation: Nature. 2005 Dec 15;438(7070):1017-21
references.pmid: 16355225
references.citation: Curr Biol. 2005 Mar 29;15(6):513-24
references.pmid: 15797019
references.citation: Brain Res Rev. 2006 Aug;51(2):161-75
references.pmid: 16412517
references.citation: Exp Cell Res. 2003 Mar 10;284(1):14-30
references.pmid: 12648463
references.citation: Nat Rev Neurosci. 2009 Jan;10(1):23-36
references.pmid: 19096368
references.citation: Life Sci. 2009 Sep 9;85(11-12):450-6
references.pmid: 19632245
references.citation: Pain. 2005 Mar;114(1-2):149-59
references.pmid: 15733640
references.citation: Circulation. 2002 Apr 2;105(13):1551-4
references.pmid: 11927521
references.citation: Eur J Pain. 2008 Jan;12(1):94-103
references.pmid: 17459743
references.citation: J Neurosci. 2007 Nov 7;27(45):12396-406
references.pmid: 17989304
references.citation: J Infect Dis. 1997 Feb;175(2):478-81
references.pmid: 9203678
references.citation: Science. 2006 Oct 27;314(5799):664-6
references.pmid: 16990514
references.citation: Breast Cancer Res. 2006;8(4):R35
references.pmid: 16839426
references.citation: Brain. 2009 Feb;132(Pt 2):288-95
references.pmid: 18567623
references.citation: Pain. 2000 Apr;85(3):425-431
references.pmid: 10781915
references.citation: J Immunol Methods. 1994 Sep 14;174(1-2):209-14
references.pmid: 8083523
references.citation: J Comp Neurol. 2001 Apr 23;433(1):86-100
references.pmid: 11283951
references.citation: Pain. 2005 May;115(1-2):71-83
references.pmid: 15836971