MCAM+ brain endothelial cells contribute to neuroinflammation by recruiting pathogenic CD4+ T lymphocytes

Abstract

The trafficking of autoreactive leukocytes across the blood-brain barrier (BBB) endothelium is a hallmark of multiple sclerosis (MS) pathogenesis. Although the BBB endothelium represents one of the main central nervous system (CNS) borders to interact with the infiltrating leukocytes, its exact contribution to neuroinflammation remains understudied. Here, we show that Mcam identifies inflammatory brain endothelial cells (ECs) with pro-migratory transcriptomic signature during experimental autoimmune encephalomyelitis (EAE). In addition, MCAM was preferentially upregulated on BBB ECs in MS lesions in situ and at EAE disease onset by molecular magnetic resonance imaging. In vitro and in vivo, we demonstrate that MCAM on BBB ECs contributes to EAE development by promoting the cellular trafficking of TH1 and TH17 lymphocytes across the BBB. Lastly, we showcase ST14 as an immune ligand to brain endothelial MCAM, enriched on CD4+ T lymphocytes that cross the BBB in vitro, in vivo and in MS lesions as detected by flow cytometry on rapid autopsy derived brain tissue from MS patients. Collectively, our findings reveal that MCAM is at the center of a pathological pathway used by brain ECs to recruit pathogenic CD4+ T lymphocyte from circulation early during neuroinflammation. The therapeutic targeting of this mechanism is a promising avenue to treat MS.

A20 regulates lymphocyte adhesion in murine neuroinflammation by restricting endothelial ICOSL expression in the CNS

“…We here identified A20-regulated ICOSL as an adhesion molecule contributing to the firm adhesion of MOG 35–55 specific proinflammatory Th1 and Th17 cells to the BBB. Although the reduction in T cell adhesion when ICOSL was blocked appeared rather mild, the effect is in line with studies investigating T cell adhesion to other adhesion molecules ( 52 , 72 ). ICOSL was only recently reported to mediate adhesion of podocytes by binding to the α V β 3 integrin through its RGD motif ( 54 ).…”

Universal method for the isolation of microvessels from frozen brain tissue: A proof-of-concept multiomic investigation of the neurovasculature

“…6 j), including notable immune factors CX3CL1, IFNGR1, CD74, IL4R, CXCL2, CXCL12, CD81, IRF1, MIF, as well as HLAs (HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-DRA, HLA-DPA1, HLA-DPB1). Moreover, adhesion molecules known to mediate cell-cell adhesion at the BBB are also present, including: CD44, previously implicated in monocyte transmigration ( He et al, 2016b ) and T-cell-endothelial cell interaction ( Flynn et al, 2013 ), MCAM, which mediates recruitment of pathogenic CD4 + T lymphocytes ( Charabati et al, 2023 ) as well as T helper (T H ) 1 cells ( Breuer et al, 2018 ), and ICAM2, which is also critical for T helper (T H ) 1 cell diapedesis ( Laschinger et al, 2002 ). Other well-characterized immune, adhesion, and trafficking molecules in our data are listed in the Supplementary data .…”

Transcriptomics and translatomics identify a robust inflammatory gene signature in brain endothelial cells after ischemic stroke

“…Mcam is involved in cell cohesion at the intercellular junctions, but under inflammatory conditions, Mcam + endothelial cells may facilitate leukocyte infiltration. Indeed, Mcam + endothelial cells promote infiltration of pathogenic CD4 + lymphocytes in a murine model of experimental autoimmune encephalomyelitis and multiple sclerosis lesions [ 31 ].…”