SDF-1α (CXCL12) regulation of lateral mobility contributes to activation of LFA-1 adhesion

Abstract

Regulation of integrin activity enables leukocytes to circulate freely, avoiding inappropriate adhesion while maintaining the ability to adhere quickly at sites of infection or inflammation. This regulation involves at least two components: affinity for ligand and affinity-independent avidity effects such as lateral mobility. Using lymphocyte function associated antigen-1 (LFA-1) as a model, we investigated the role of integrin release from cytoskeletal motion constraints in response to the chemokine stromal cell-derived factor-1 (SDF-1α) in this process. All experiments were done in primary T cells to avoid nonphysiological activation processes often seen with the use of cell lines. We found that SDF-1α releases LFA-1 from cytoskeletal constraints as effectively as does cytochalasin D. The resultant increased diffusion is correlated with a robust increase in LFA-1-mediated adhesion under physiological shear stress. We further investigated the role of the highly conserved GFFKR sequence in the LFA-1 cytoplasmic domain. We report that the GFFKR sequence is both necessary and sufficient for regulation of the SDF-1α-triggered proadhesive release from cytoskeleton interactions. While this does not address the role of transient SDF-1α-induced conformational changes in the activation process, these results strongly suggest that any model of chemokine-induced LFA-1 activation must take into account chemokine-induced integrin lateral mobility. In addition, these results have ramifications for models of differential binding of LFA-1 to surface-bound vs. soluble intercellular adhesion molecule-1.

VLA-4 phosphorylation during tumor and immune cell migration relies on its coupling to VEGFR2 and CXCR4 by syndecan-1

“…The cells adhere to ICAM-1 via LFA-1 ( Fig. 7C) and their attachment is blocked by LFA-1-inhibitory antibodies, but this requires treatment with SDF-1, consistent with previously published reports (Peled et al, 2000;Wu et al, 2012). Although the mechanism of LFA-1 activation by SDF-1 is unknown, it does not appear to involve its binding to CXCR4 as AMD3100 fails to inhibit attachment ( Fig.…”

Integrin Regulation during Leukocyte Recruitment

“…This increase in avidity may represent a trigger event for outside-in signaling, thus marking a crucial event for postadhesion strengthening (33). Lateral movement of LFA-1 in T cells requires active release from cytoskeletal constraints after GPCR engagement (34). Furthermore, Ca 2+ flux was shown to be essential for integrin clustering (35).…”

CXCR4/CXCR7 Molecular Involvement in Neuronal and Neural Progenitor Migration: Focus in CNS Repair

“…Alternatively, CXCL12 is concentrated by heparan sulfate proteoglycans (Amara et al, ; Netelenbos et al, ) and LFA‐1 (lymphocyte function associated antigen‐1), as well as by other cell adhesion molecules involved in CXCL12 triggered proadhesive interactions in T lymphocytes (Wu et al, ).…”

“…Regulation of integrin activity maintains the ability of lymphocytes to adhere quickly at sites of infection or inflammation (Wu et al, ). Indeed, quiescent type B NSCs are the only cell type that do not display chemotaxis toward CXCL12 or endothelial cell‐conditioned medium.…”