Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1α 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-1 alpha (CXCL12) is over-expressed and might attract monocytes into the CNS. We demonstrate here that SDF-1 alpha stimulates migration of monocytes through its receptor, CXCR4, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for 132 integrins. SDF-1 alpha also decreases monocyte adherence to brain microvascular endothelial cells (BMVEC) that are activated with TNF-alpha, IL-1 beta, or recombinant envelope glycoprotein from HIV-1, which increase BMVEC expression of ICAM-L The decreased adherence is linked to down-regulation on monocytes of the activation-dependent epitope of the 13, integrin LFA-1 by SDF-1 alpha. Knockdown of Lyn in monocytes using small interfering RNA decreases SDF-1 alpha-mediated migration and prevents the inhibition of monocyte attachment to ICAM-1 and activated BMVEC. Thus, in SDF-1 alpha-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.