Endothelial basement membrane laminin α5 selectively inhibits T lymphocyte extravasation into the brain

Abstract

Specific inhibition of the entry of encephalitogenic T lymphocytes into the central nervous system in multiple sclerosis would provide a means of inhibiting disease without compromising innate immune responses. We show here that targeting lymphocyte interactions with endothelial basement membrane laminins provides such a possibility. In mouse experimental autoimmune encephalomyelitis, T lymphocyte extravasation correlates with sites expressing laminin alpha4 and small amounts of laminin alpha5. In mice lacking laminin alpha4, laminin alpha5 is ubiquitously expressed along the vascular tree, resulting in marked and selective reduction of T lymphocyte infiltration into the brain and reduced disease susceptibility and severity. Vessel phenotype and immune response were not affected in these mice. Rather, laminin alpha5 directly inhibited integrin alpha(6)beta(1)-mediated migration of T lymphocytes through laminin alpha4. The data indicate that T lymphocytes use mechanisms distinct from other immune cells to penetrate the endothelial basement membrane barrier, permitting specific targeting of this immune cell population.

Endothelial basement membrane laminin 511 is essential for shear stress response

“…Immunofluorescence staining for basement membrane components and interstitial matrix molecules, including fibronectin and collagen type I, showed no differences between WT, Lama4 −/− and Tek‐Cre::Lama5 −/− arteries in staining intensities or patterns for any of the molecules tested (Fig 2 and Appendix Fig S2B, Table 1). Only Lama4 −/− mice, which have been previously characterized (Thyboll et al , 2002), show an aberrant ubiquitous expression of laminin α5 in all endothelial basement membranes (Wu et al , 2009). …”

“…Importantly, the resistance arteries of the Tek‐Cre::Lama5 −/− did not reveal any compensatory expression of other ECM molecules such as fibronectin, which has been previously shown to be required for shear detection and adhesion complex remodelling in in vitro studies. Only Lama4 −/− arteries showed an aberrant ubiquitous expression of laminin α5 throughout the endothelial cell basement membrane (Wu et al , 2009), and a hypersensitive response to shear. Our in vivo data therefore support a direct effect of laminin 511 on endothelial cell shear stress response.…”

“…Laminin 411 is ubiquitously expressed in all endothelial basement membranes from the first stages of tube formation (Hallmann et al , 2005) and has been shown to play a role in angiogenesis in some tissues (Stenzel et al , 2011). By contrast, laminin α5 first appears surrounding arteries when the heart commences to beat (E10) and when blood pressure is initiated, and only much later in basement membranes of microvessels (Sorokin et al , 1997); it has been implicated in immune cell extravasation (Sixt et al , 2001a; Wu et al , 2009). Both laminin isoforms have been reported to interact with β1‐integrins (Kikkawa et al , 2000; Nielsen & Yamada, 2001; Sixt et al , 2001b) and laminin 511 also with the RGD‐binding integrins (Sasaki & Timpl, 2001).…”

The Blood–Brain Barrier

“…These BMs are comprised of different secreted molecules including type IV collagens, laminin, nidogen, heparin sulfate proteoglycans, and other glycoproteins. The vascular and parenchymal BMs have a different composition, for instance, the former is made up of laminins a4 and a5, whereas the latter contains laminins a1 and a2 (Wu et al 2009;Sorokin 2010). These BMs provide an anchor for many signaling processes at the vasculature, but also provide an additional barrier for molecules and cells to cross before accessing the neural tissue.…”

Basement Membranes: Cell Scaffoldings and Signaling Platforms

“…Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004911 (Wu et al 2009). The integrin specificity is somewhat surprising given that a5-laminins, unlike a4-laminins, are strong substrates for a6b1.…”