CCR5 expression on monocytes and T cells: Modulation by transmigration across the blood–brain barrier in vitro

Abstract

Observational studies in multiple sclerosis (MS) demonstrated altered expression of chemokine receptors (CkRs) on comparable populations of mononuclear cells (e.g. CD4 + /CD45RO + T-cells) in brain sections compared with blood. These findings raised questions about the regulation of CkRs on trafficking cells. Regulatory processes for CkRs are complex: examples include down-regulation following ligand engagement during migration and either up-or down-regulation following activation. Additionally, CkRs that mediate transmigration without being down-regulated will be selectively enriched on migrating cells in the inflammatory site. Finally, CkRs may act as functionally neutral markers of activated cells capable of undergoing transmigration. Clarifying CkR regulation may aid in the selection and application of antagonists for treating neuroinflammation. Mechanisms of receptor regulation during transmigration cannot be studied by descriptive methods. We evaluated CCR5 expression on CD14+ monocytes and CD3+ T-cells following CCL5-driven transmigration through an in vitro blood-brain barrier (IVBBB), as both T-cells and monocytes in MS lesions express CCR5. CCR5 expression was augmented on non-migrating CD14+ but not CD3+ cells, suggesting selective activation of monocytes by incubation in contact with endothelial cells. As proposed from observational studies, CCR5 was enriched on monocytes that migrated spontaneously in the absence of exogenous chemokine. Addition of the CCR5 ligand CCL5 to the lower chamber led to enhanced CD3+ T-cell migration. Interestingly, CCR5 was down-regulated on both CD14+ monocytes and CD3+ T cells during CCL5-driven migration. These results are distinct from those obtained in comparable studies of CCR2 and CXCR3, suggesting that the specifics for CkR expression should be studied for individual receptors on each leukocyte subpopulation during the design of strategies for pharmacological blockade in neuroinflammation.

Modulation of cell proliferation, survival and gene expression by RAGE and TLR signaling in cells of the innate and adaptive immune response: role of p38 MAPK and NF-KB

“…expression of CCR5 in T lymphocytes was lower in comparison with monocytes, as expected based on the literature 26,31 . RAGE and TLR4 stimulation, alone and associated, decreased CCR5 gene expression in T lymphocytes, whereas the combined activation of these receptors did not affect CCR5 expression in monocytes.…”

Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury

“…The observation that peak macrophage infiltration precedes peak T cell entry is a pattern we have also observed in the denervated hippocampus (15,43) and after cuprizone-induced demyelination (60). It is unlikely that initial increases in T cell and macrophage proportions may have simply reflected efflux due to physical damage of the blood-brain barrier by the stab injury, because T cells outnumber monocytes in peripheral blood (75). It is even more apparent that inherent mechanisms control leukocyte recruitment to the injured brain beyond 3 h, because the patterns of response were temporally and quantitatively different.…”

Chemokines and relapses in childhood acute lymphoblastic leukemia: A role in migration and in resistance to antileukemic drugs

“…Examples are CCR5 [27,28], CCR8 [29], CCR6, and CCR7 [30,31]. There is scant information available on chemokine receptor and leukemic infiltration of organs.…”