Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1 alpha through Lyn kinase.
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.
Malik
Mobeen
M
Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
Chen
Ying-Yu
YY
Kienzle
Martha F
MF
Tomkowicz
Brian E
BE
Collman
Ronald G
RG
Ptasznik
Andrzej
A
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*
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
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