title: Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1 alpha through Lyn kinase.
abstract: Infiltration of activated monocytes into the brain is a prerequisite for the development of various neurological disorders such as HIV-associated dementia, multiple sclerosis, and other inflammatory processes. In these pathologies, the chemokine SDF-1alpha (CXCL12) is over-expressed and might attract monocytes into the CNS. We demonstrate here that SDF-1alpha stimulates migration of monocytes through its receptor, CXCR4, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for beta(2) integrins. SDF-1alpha also decreases monocyte adherence to brain microvascular endothelial cells (BMVEC) that are activated with TNF-alpha, IL-1beta, or recombinant envelope glycoprotein from HIV-1, which increase BMVEC expression of ICAM-1. The decreased adherence is linked to down-regulation on monocytes of the activation-dependent epitope of the beta(2) integrin LFA-1 by SDF-1alpha. Knockdown of Lyn in monocytes using small interfering RNA decreases SDF-1alpha-mediated migration and prevents the inhibition of monocyte attachment to ICAM-1 and activated BMVEC. Thus, in SDF-1alpha-stimulated monocytes, Lyn acts as a positive regulator of migration and a negative regulator of adhesion to BMVEC through the LFA-1 integrin. These results provide a novel Lyn-mediated signaling mechanism for the regulation of monocyte movement at the blood-brain barrier.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Mobeen
authors.initials: M
authors.lastname: Malik
authors.forename: Ying-Yu
authors.initials: YY
authors.lastname: Chen
authors.forename: Martha F
authors.initials: MF
authors.lastname: Kienzle
authors.forename: Brian E
authors.initials: BE
authors.lastname: Tomkowicz
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Collman
authors.forename: Andrzej
authors.initials: A
authors.lastname: Ptasznik
mesh_terms: D001921:Brain / Q000098:blood supply* / Q000166:cytology / Q000201:enzymology; D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002464:Cell Migration Inhibition / Q000276:immunology; D054377:Chemokine CXCL12 / Q000378:metabolism / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000502:physiology*; D008833:Microcirculation / Q000276:immunology; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology*
chemical_list: D018821:CD18 Antigens; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D019718:Receptors, CXCR4; D018799:Intercellular Adhesion Molecule-1; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases
references.citation: Am J Pathol. 1999 Nov;155(5):1599-611
references.pmid: 10550317
references.citation: J Neuroimmunol. 2004 Dec;157(1-2):140-6
references.pmid: 15579291
references.citation: Blood. 2001 Nov 15;98(10):2909-16
references.pmid: 11698270
references.citation: J Exp Med. 2002 Sep 2;196(5):667-78
references.pmid: 12208881
references.citation: J Neuropathol Exp Neurol. 2003 Jun;62(6):617-26
references.pmid: 12834106
references.citation: Science. 2003 Oct 3;302(5642):103-6
references.pmid: 14526080
references.citation: Science. 2003 Dec 5;302(5651):1704-9
references.pmid: 14657486
references.citation: Lab Invest. 2003 Dec;83(12):1787-98
references.pmid: 14691297
references.citation: Cell. 1987 Dec 4;51(5):813-9
references.pmid: 3315233
references.citation: J Immunol. 1989 May 15;142(10):3553-9
references.pmid: 2541200
references.citation: Nature. 1990 Aug 2;346(6283):425-34
references.pmid: 1974032
references.citation: Am J Pathol. 1992 Jan;140(1):137-44
references.pmid: 1731520
references.citation: J Exp Med. 1992 Dec 1;176(6):1703-18
references.pmid: 1460427
references.citation: Neurosci Lett. 1994 Feb 28;168(1-2):201-4
references.pmid: 7913216
references.citation: J Biol Chem. 1996 Jan 12;271(2):695-701
references.pmid: 8557675
references.citation: J Immunol. 1996 Mar 1;156(5):1810-7
references.pmid: 8596031
references.citation: Int J Parasitol. 1996 Jun;26(6):647-55
references.pmid: 8875310
references.citation: Mol Med. 1997 Aug;3(8):553-64
references.pmid: 9307983
references.citation: J Immunol. 1998 Oct 15;161(8):4309-17
references.pmid: 9780207
references.citation: J Immunol. 1998 Dec 15;161(12):6896-903
references.pmid: 9862722
references.citation: Neuropathol Appl Neurobiol. 1998 Dec;24(6):461-7
references.pmid: 9888156
references.citation: Am J Pathol. 1999 Jan;154(1):45-51
references.pmid: 9916917
references.citation: J Leukoc Biol. 2005 Oct;78(4):1016-23
references.pmid: 16081599
references.citation: Expert Rev Mol Med. 2005 Dec 2;7(27):1-26
references.pmid: 16321172
references.citation: Brain Res. 2005 Dec 7;1064(1-2):21-31
references.pmid: 16289483
references.citation: Brain. 2006 Jan;129(Pt 1):200-11
references.pmid: 16280350
references.citation: Blood. 2006 Jun 1;107(11):4234-9
references.pmid: 16467205
references.citation: Eur J Clin Invest. 2006 Jul;36(7):447-58
references.pmid: 16796601
references.citation: J Neuroimmunol. 2006 Aug;177(1-2):27-39
references.pmid: 16782208
references.citation: Glia. 2006 Nov 1;54(6):619-29
references.pmid: 16944452
references.citation: Mol Cell Biol. 2006 Oct;26(19):7130-44
references.pmid: 16980616
references.citation: Immunity. 2006 Dec;25(6):907-18
references.pmid: 17174122
references.citation: J Neurovirol. 2007 Jun;13(3):242-51
references.pmid: 17613714
references.citation: Neurotherapeutics. 2007 Oct;4(4):590-601
references.pmid: 17920540
references.citation: Prog Neurobiol. 2008 Feb;84(2):116-31
references.pmid: 18177992
references.citation: Biochem Soc Trans. 2008 Apr;36(Pt 2):229-34
references.pmid: 18363565
references.citation: Blood. 2008 May 15;111(10):5182-6
references.pmid: 18339898
references.citation: Nature. 2001 Apr 19;410(6831):988-94
references.pmid: 11309629