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

Mario Amatruda; Candice Chapouly; Viola Woo; Farinaz Safavi; Joy Zhang; David Dai; Anthony Therattil; Chang Moon; Jorge Villavicencio; Alexandra Gordon; Charles Parkos; Sam Horng

doi:10.1093/braincomms/fcac044

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

Brain Commun. 2022 Feb 18;4(2):fcac044. doi: 10.1093/braincomms/fcac044. eCollection 2022.

Authors

Mario Amatruda¹, Candice Chapouly², Viola Woo¹, Farinaz Safavi³, Joy Zhang⁴, David Dai⁵, Anthony Therattil⁶, Chang Moon¹, Jorge Villavicencio¹, Alexandra Gordon⁷, Charles Parkos⁸, Sam Horng^{1

9}

Affiliations

¹ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Univ. Bordeaux, Inserm, Biology of Cardiovascular Diseases, U1034, CHU de Bordeaux, F-33604 Pessac, France.
³ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁴ University of Virginia School of Medicine, Charlottesville, VA, USA.
⁵ Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁶ New York Medical College, Valhalla, NY, USA.
⁷ Miller School of Medicine at University of Miami, Miami, FL, USA.
⁸ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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, 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 junctional adhesion molecule-A in regulating CNS autoinflammatory disease. In cell co-cultures, we found that junctional adhesion molecule-A-mediated signalling between astrocytes and T cells increases levels of matrix metalloproteinase-2, C-C motif chemokine ligand 2 and granulocyte-macrophage colony-stimulating factor, pro-inflammatory 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-A^fl/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 with wild-type controls (JAM-A^fl/fl ). Treatment of wild-type mice with intraperitoneal injection of soluble junctional adhesion molecule-A blocking peptide decreases the severity of experimental autoimmune encephalomyelitis, highlighting the potential of contact-mediated astrocyte-immune cell signalling as a novel translational target against neuroinflammatory disease.

Keywords: astrocyte immune cell cross-talk; experimental autoimmune encephalomyelitis; glia limitans; junctional adhesion molecule-A; multiple sclerosis.

Abstract

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