Laminin-411 Is a Vascular Ligand for MCAM and Facilitates TH17 Cell Entry into the CNS

Abstract

TH17 cells enter tissues to facilitate pathogenic autoimmune responses, including multiple sclerosis (MS). However, the adhesion molecules involved in the unique migratory capacity of TH17 cells, into both inflamed and uninflamed tissues remain unclear. Herein, we characterize MCAM (CD146) as an adhesion molecule that defines human TH17 cells in the circulation; following in vitro restimulation of human memory T cells, nearly all of the capacity to secrete IL-17 is contained within the population of cells expressing MCAM. Furthermore, we identify the MCAM ligand as laminin 411, an isoform of laminin expressed within the vascular endothelial basement membranes under inflammatory as well as homeotstatic conditions. Purified MCAM-Fc binds to laminin 411 with an affinity of 27 nM, and recognizes vascular basement membranes in mouse and human tissue. MCAM-Fc binding was undetectable in tissue from mice with targeted deletion of laminin 411, indicating that laminin 411 is a major tissue ligand for MCAM. An anti-MCAM monoclonal antibody, selected for inhibition of laminin binding, as well as soluble MCAM-Fc, inhibited T cell adhesion to laminin 411 in vitro. When administered in vivo, the antibody reduced TH17 cell infiltration into the CNS and ameliorated disease in an animal model of MS. Our data suggest that MCAM and laminin 411 interact to facilitate TH17 cell entry into tissues and promote inflammation.

Soluble Melanoma Cell Adhesion Molecule (sMCAM/sCD146) Promotes Angiogenic Effects on Endothelial Progenitor Cells through Angiomotin

“…Although it has been reported that CD146 acts as a homophilic adhesion molecule, we (4) and others (25) have not been able to show a direct interaction between sCD146 and membrane CD146 or between membrane CD146 and itself. Along this line, two different heterophilic ligands of membrane CD146 have been recently described.…”

VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells

“…It is clear that T H 17 cells have additional adhesive mechanisms that permit CNS entry even in the presence of natalizumab. LFA-1 is likely to play an important role, consistent with the findings of Rothhammer et al (Rothhammer et al, 2011) in EAE using conditional 4 integrin knockout mice and potentially also MCAM/laminin, which is consistent with the results from Flanagan et al (2012) and . We hypothesize that the cells that are still able to enter the CSF in natalizumab-treated patients are most likely to be T H 17 cells, suggesting a role for this population not only in FCS and Hepes).…”

“…Our study supports the relevance of these findings in the human system as MCAM + memory cells (T H 17 cells; Flanagan et al, 2012;Larochelle et al, 2012) could still adhere to endothelium under CD49d-blocking conditions. An additional blockade of LFA-1 could abrogate this adhesion, in accordance with previously published data, suggesting that LFA-1 is important for the CNS infiltration of all T cells (Rothhammer et al, 2011).…”

“…As recent studies have shown that T H 17-polarized cells can induce experimental autoimmune encephalomyelitis (EAE) in CD49d-deficient mice (Rothhammer et al, 2011) and that T H 17 cells use VLA-4-independent mechanisms to access the CNS during viral infection (Rothhammer et al, 2014), we next investigated whether T H 17 cells could enter the CSF under LTNT conditions in the human system. The melanoma cell adhesion molecule (MCAM; CD146) was recently shown to be a highly specific extracellular marker for T H 17 cells in humans Flanagan et al, 2012), opening the possibility of functional analysis of rolling and adhesion of T H 17/MCAM + cells. By examining healthy controls' PBMC under shear flow conditions, we could show that blockade of CD49d by natalizumab abrogated the adhesion of MCAM  memory cells (CD3 + CD4 + CD45RO + MCAM  ) but did not affect adhesion of MCAM + memory cells (Fig.…”

Dual role of ALCAM in neuroinflammation and blood–brain barrier homeostasis

“…Although the roles of ICAM-1 and VCAM-1 during leukocyte transmigration in most vascular beds have been extensively studied (8)(9)(10), additional adhesion molecules have also been shown to partake in the transmigration process of encephalitogenic immune cells, including activated leukocyte cell adhesion molecule (ALCAM/CD166) (11,12), melanoma cell adhesion molecule (MCAM) (13)(14)(15), mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) (16,17), vascular adhesion protein (VAP-1) (18,19), Ninjurin-1 (20), and JAM-L (21). We have previously demonstrated that ALCAM is part of a group of adhesion molecules, found on BBB endothelial cells (BBB-ECs), that are involved in immune cell diapedesis (11,12).…”