Astrocytic junctional adhesion molecule-A regulates T-cell entry past the glia limitans to promote central nervous system autoimmune attack

Abstract

Contact mediated interactions between the astrocytic endfeet and infiltrating immune cells within the perivascular space are underexplored, yet represent potential regulatory check-points against CNS autoimmune disease and disability. Reactive astrocytes upregulate Junctional Adhesion Molecule-A (JAM-A), an immunoglobulin-like cell surface receptor that binds to T cells via its ligand, the integrin, lymphocyte function-associated antigen-1. Here, we tested the role of astrocytic JAM-A in regulating CNS autoinflammatory disease. In cell co-cultures, we found that JAM-A mediated signaling between astrocytes and T cells increases levels of matrix metalloproteinase-2, C-C motif chemokine ligand 2 and granulocyte-macrophage colony-stimulating factor, proinflammatory factors driving lymphocyte entry and pathogenicity in multiple sclerosis and experimental autoimmune encephalomyelitis, an animal model of CNS autoimmune disease. In experimental autoimmune encephalomyelitis, mice with astrocyte-specific JAM-A deletion (mGFAP:CreJAM-Afl/fl) exhibit decreased levels of matrix metalloproteinase-2, reduced ability of T cells to infiltrate the CNS parenchyma from the perivascular spaces, and a milder histopathological and clinical course of disease compared to wild-type controls (JAM-Afl/fl). Treatment of wild-type mice with intraperitoneal injection of soluble JAM-A blocking peptide decreases the severity of experimental autoimmune encephalomyelitis, highlighting the potential of contact mediated astrocyte-immune cell signaling as a novel translational target against neuroinflammatory disease.

Junctional adhesion molecule‐A deficient mice are protected from severe experimental autoimmune encephalomyelitis

“…Furthermore, as previously observed on endothelial cells, inflammatory stimuli release JAM‐A from the astrocyte tight junctions, leading to a more dispersed cell surface expression and making JAM‐A accessible for engagement by immune cells [48]. Mice lacking JAM‐A specifically in astrocytes were observed to develop ameliorated aEAE by trapping T cells in PVS underscoring a role for JAM‐A in mediating T‐cell migration across the perivascular glia limitans [48]. Lack of JAM‐A in astrocytes cocultured with T cells revealed a decrease of the inflammatory effector molecules such as CCL2, GM‐CSF, and MMP‐2, with proven roles in immune cell entry into the CNS parenchyma during EAE [48].…”

“…JAM‐A expression on astrocytes was previously shown to contribute to T‐cell migration across the glia limitans into the CNS parenchyma [48]. This second step in immune cell migration across the glia limitans into the CNS parenchyma is crucial for inducing clinial disease in EAE in C57BL/6J mice [49].…”

“…Interestingly, it was previously reported that reactive astrocytes can upregulate expression of the tight junctional molecules claudin-1, claudin-4, and JAM-A and form tight junctions between their aquaporin-4 + end-feet at the level of the glia limitans upon asymptomatic inflammatory focal lesion induction as well as in aEAE [48,69]. Furthermore, as previously observed on endothelial cells, inflammatory stimuli release JAM-A from the astrocyte tight junctions, leading to a more dispersed cell surface expression and making JAM-A accessible for engagement by immune cells [48]. Mice lacking JAM-A specifically in astrocytes were observed to develop ameliorated aEAE by trapping T cells in PVS underscoring a role for JAM-A in mediating T-cell migration across the perivascular glia limitans [48].…”

“…Mice lacking JAM‐A specifically in astrocytes were observed to develop ameliorated aEAE by trapping T cells in PVS underscoring a role for JAM‐A in mediating T‐cell migration across the perivascular glia limitans [48]. Lack of JAM‐A in astrocytes cocultured with T cells revealed a decrease of the inflammatory effector molecules such as CCL2, GM‐CSF, and MMP‐2, with proven roles in immune cell entry into the CNS parenchyma during EAE [48]. These previous data highlight the barrier function of the glia limitans in limiting T‐cell infiltration into the CNS parenchyma and combined with our observations show that JAM‐A mediates T‐cell migration across the glia limitans rather than the BBB.…”

Astrogliosis in multiple sclerosis and neuro-inflammation: what role for the notch pathway?

“…Subsequent work in EAE also showed that junctional adhesion molecule-A (JAM-A), in addition to its function as a tight junction, also plays a role in astrocyte-T cell communication and promotes the passage of the latter from the perivascular space into the parenchyma ( 76 ).…”