Endothelial Cell Integrin Laminin Receptor Expression in Multiple Sclerosis Lesions

Abstract

Laminin , a major glycoprotein component of vessel basement membranes , is recognized by ␤ 1 -and ␤ 3 -integrins expressed on endothelial cells. To determine how endothelial cell integrins might function in multiple sclerosis (MS) lesions , integrin laminin receptors and laminin were analyzed in central nervous system samples from MS patients and controls by immunohistochemistry. In active MS lesions , endothelial cell VLA-6 and ␤ 1 subunits were decreased compared to controls whereas ␣ v subunit and VLA-1 were increased. In chronic inactive lesions ␤ 1 , VLA-6 and ␣ v were the same as controls but VLA-1 remained increased. ␣ 3 subunit was constant in all samples. By immunoelectron microscopy VLA-1 , VLA-6 , ␤ 1 , and laminin were distributed throughout endothelial cells; ␣ v was adjacent to and on luminal surfaces; ␣ v and VLA-1 were on intercellular junctions. These results indicate distinct regulation and functions of these integrins in different lesion stages. In active lesions decreased endothelial cell ␤ 1 /VLA-6 could result in their detachment from laminin thereby facilitating leukocyte transvascular migration and bloodbrain barrier breakdown. Laminins (Ln) are major glycoprotein components of extracellular matrix and vessel basement membranes (BM).1 Peptide sequences of Ln and of other extracellular matrix molecules are recognized by ␣ 1 ␤ 1 (VLA-1), ␣ 2 ␤ 1 (VLA-2), ␣ 3 ␤ 1 (VLA-3), ␣ 6 ␤ 1 (VLA-6), ␣ 6 ␤4, and ␣ v ␤ 3 integrins expressed on the surfaces of many cell types. 2,3Integrin-mediated recognition of extracellular matrix molecules results in intracellular signaling that affects a range of cell behaviors. 4 In endothelial cells these signals affect focal adhesions and cytoskeletal organization, ie, actin fiber assembly. Therefore, integrin-mediated endothelial cell recognition of Ln and other BM molecules may determine cell-to-cell adhesiveness and mediate behaviors such as spreading, retraction, polarization, and migration that are essential for the maintenance and normal functioning of blood vessels. 5-7Inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor-␣ (TNF-␣), interferon-␥ (IFN␥), and transforming growth factor-␤ (TGF␤), growth factors such as fibroblast growth factor, and reactive oxygen intermediates induce changes in the levels and surface distribution of endothelial cell integrins in vitro. 8 -13 In immune reactions these alterations likely affect endothelial cell recognition of BM molecules and result in contraction of the endothelial cells, producing defects or denudation of the vascular lining. Cytokines may also be bound by Ln 14 and influence extracellular matrix turnover. 15,16 Thus, both endothelial cell integrin expression and the BM may undergo numerous modifications over the course of cellular immune reactions. Indeed, in diverse inflammatory conditions alterations of endothelial cell integrin Ln receptor expression have been documented. [17][18][19][20] These studies suggest that endothelial cell integrin expression changes over time in complex patt...

Magnetic Resonance Imaging Reveals Therapeutic Effects of Interferon-Beta on Cytokine-Induced Reactivation of Rat Model of Multiple Sclerosis

“…As previously suggested, this increase in rCBV may reflect a combination of processes such as reactivation of metabolically active leukocytes, local production of the vasodilator nitric oxide, and increased expression of local cytokines, which are known to induce blood vessel dilation by changing the expression of endothelial integrins. 39 At the same early time point as for the increase in CBV, an increase in ADC within the corpus callosum of frrMOG-EAE animals was apparent, but in this case it persisted throughout the time period studied. This increase in ADC was not associated with either an increase in T 2 or BBB breakdown, suggesting that this reflects disruption of callosal integrity giving rise to less restricted diffusion, rather than frank vasogenic edema.…”

The extracellular matrix in multiple sclerosis: an update

“…This localization may be modulated directly by the ECM (9) or indirectly as a consequence of ECM binding and presentation of soluble inflammatory mediators, e.g., tumor necrosis factor-a (Kuruganti PA, Hinojoza JR, Ehmann RA and Sobel RA, unpublished results). Altered expression of the integrin laminin receptors VLA-6 and VLA-1 in MS lesions may also result in endothelial cell retraction and detachment from vascular basement membrane laminin leading to increased permeability of the blood-brain barrier (10). Furthermore, up-regulation of molecules associated with endothelial cell injury, e.g., plasminogen activator inhibitor-1, urokinase plasminogen activator and matrix metalloproteinases (MMPs), is likely to facilitate leukocyte passage through blood vessel walls as the basement membrane ECM undergoes remodeling (11).…”

Increased expression of the β4 and α5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-α in the central nervous system

“…Investigation of the underlying mechanisms have revealed that pro-inflammatory cytokines regulate several aspects of vascular cell behavior, including cell proliferation, migration, differentiation, and vascular permeability (Grau et al 1989;Stanimirovic and Satoh 2000). Significantly, the expression and function of vascular cell integrins is regulated both during chronic inflammation in vivo (Previtali et al 1997;Sobel et al 1998;Kloss et al 1999), and by individual cytokines in vitro (Defillipi et al 1992;Frank et al 1996). Specifically, integrin expression on cerebral blood vessels is decreased during focal cerebral ischemia Wagner et al 1997;Tagaya et al 2001) and acute demyelination events (Sobel et al 1998), but is increased during chronic inflammatory events in the demyelinating animal model, experimental autoimmune encephalomyelitis (EAE) (Previtali et al 1997), and in the facial motor nucleus lesion model (Kloss et al 1999).…”

“…Significantly, the expression and function of vascular cell integrins is regulated both during chronic inflammation in vivo (Previtali et al 1997;Sobel et al 1998;Kloss et al 1999), and by individual cytokines in vitro (Defillipi et al 1992;Frank et al 1996). Specifically, integrin expression on cerebral blood vessels is decreased during focal cerebral ischemia Wagner et al 1997;Tagaya et al 2001) and acute demyelination events (Sobel et al 1998), but is increased during chronic inflammatory events in the demyelinating animal model, experimental autoimmune encephalomyelitis (EAE) (Previtali et al 1997), and in the facial motor nucleus lesion model (Kloss et al 1999). When taken together with the role of the ECM in regulating vascular function (Eliceiri and Cheresh 1999;Hynes et al 1999;Kim et al 2000;Milner and Campbell 2002b), this suggests that dynamic alterations in integrin expression might contribute to some of the vascular changes observed during these conditions.…”