Vimentin function in lymphocyte adhesion and transcellular migration

Abstract

Although the adhesive interactions of leukocytes with endothelial cells are well understood, little is known about the detailed mechanisms underlying the actual migration of leukocytes across the endothelium (diapedesis). Leukocytes have been shown to use both paracellular and transcellular routes for transendothelial migration. Here we show that peripheral blood mononuclear cells (PBMCs; T- and B-lymphocytes) preferentially use the transcellular route. The intermediate filaments of both endothelial cells and lymphocytes formed a highly dynamic anchoring structure at the site of contact between these two cell types. The initiation of this process was markedly reduced in vimentin-deficient (vim(-/-)) PBMCs and endothelial cells. When compared with wild-type PBMCs, vim(-/-) PBMCs showed a markedly reduced capacity to home to mesenteric lymph nodes and spleen. Furthermore, endothelial integrity was compromised in vim(-/-) mice, demonstrating that intermediate filaments also regulate the barrier that governs leukocyte extravasation. Absence of vimentin resulted in highly aberrant expression and distribution of surface molecules critical for homing (ICAM-1 and VCAM-1 on endothelial cells and integrin-beta1 on PBMCs). These data show that intermediate filaments are active in lymphocyte adhesion and transmigration.

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

“…Indeed, it is possible that, different from the chemokines used in our study, stimuli with broader effects, such as LPS or carrageenan, overcome vimentin requirement for efficient extravasation. Consistent with this view, Nieminen et al [31] describe that the lack of vimentin specifically affects homing of lymphocytes in vivo, a process strictly depending on selected chemokines. Nonetheless, the in vivo outcome of PI3Kg-dependent vimentin phosphorylation is yet unclear and needs further future investigation.…”

“…Phosphorylation of vimentin Ser6, as well as its surrounding serines, and the subsequent filament disassembly play a crucial role in transendothelial cell migration [27,30,31]; therefore, the function of PI3Kg in this process was analyzed. In the presence of a CCL5 gradient, transmigration through TNF-a-activated HUVECs of PI3Kg-null BMDM was significantly impaired as compared with WT controls (46.1 and 32.4% reduction at 30 min and 4 h, respectively; po0.01, two-tailed Student's t test, n 5 3).…”

“…Nonetheless, fibroblasts from vimentindeficient mice show mechanical instability and impaired ability to migrate and to contract a 3-D collagen network [29], thus providing a genetic evidence for the involvement of vimentin in cell plasticity and motility [30,31]. More recent results further confirm this view and indicate that control of vimentin phosphorylation is crucial for cell migration [19,27].…”

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

“…6,12 In breast cancer, in particular, vimentin positive tumors were observed in younger women, usually lacked estrogen and progesterone receptors, and correlated with high-grade cancer 13 and tumor size. 14 Studies done in vitro show that vimentin is essential for cell motility and migration, loss of vimentin expression nearly eliminates cell migration 5,[15][16][17] and increased expression enhances migration. 10,16,18 Furthermore, a vimentin knockout mouse has defective cell migration 19 without other obvious phenotypic consequences.…”

Vimentin Intermediate Filaments: the Central Base in Sinus Endothelial Cells of the Rat Spleen

“…In migration of lymphocytes through endothelial cells, vimentin networks of these two cells types play a crucial role in the transcellular migration at the site of contact (Nieminen et al, 2006). The absence of vimentin either in endothelial cells or in lymphocytes significantly reduces the adhesion of these cell-types to each other and this is considered to result from decreased amount of the adhesion molecules both on the endothelial cells and lymphocytes.…”