Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1 alpha through Lyn kinase

J Immunol. 2008 Oct 1;181(7):4632-7. doi: 10.4049/jimmunol.181.7.4632.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain / blood supply*
  • Brain / cytology
  • Brain / enzymology
  • CD18 Antigens / metabolism
  • Cell Adhesion / immunology
  • Cell Migration Inhibition / immunology
  • Chemokine CXCL12 / metabolism
  • Chemokine CXCL12 / physiology*
  • Chemotaxis, Leukocyte / immunology*
  • Down-Regulation / immunology
  • Endothelium, Vascular / cytology*
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / immunology
  • Humans
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Ligands
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Lymphocyte Function-Associated Antigen-1 / physiology*
  • Microcirculation / immunology
  • Monocytes / enzymology
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Receptors, CXCR4 / metabolism
  • Receptors, CXCR4 / physiology
  • Signal Transduction / immunology
  • src-Family Kinases / metabolism
  • src-Family Kinases / physiology*

Substances

  • CD18 Antigens
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Ligands
  • Lymphocyte Function-Associated Antigen-1
  • Receptors, CXCR4
  • Intercellular Adhesion Molecule-1
  • lyn protein-tyrosine kinase
  • src-Family Kinases