Contributions
Abstract: P502
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 18 Neurobiology
Junctional Adhesion Molecule-A (JAM-A) is a versatile cell surface molecule involved in tight junction formation, leukocyte adhesion and signal transduction. During CNS inflammation, leukocytes must traverse the endothelial blood-brain barrier (BBB) and the astrocytic glial limitans (GL) in order to access the parenchyma and induce damage. Recently, we have found that reactive astrocytes at the GL upregulate JAM-A in vitro and in vivo. We hypothesized that astrocytic JAM-A mediates leukocyte adhesion and facilitates cell trafficking into the CNS parenchyma, and thus lesion pathogenesis and clinical disability. To selectively delete JAM-A from reactive astrocytes, we created a conditional JAM-A knock-out (CKO) mouse line by crossing mGFAP:Cre mice with JAM-Afl/fl mice. To test the importance of astrocytic JAM-A in CNS inflammatory lesion pathogenesis, we induced two models of CNS inflammatory disease in CKO mice and controls: 1) cortical injections of adenovirally mediated IL-1 (AdIL-1) and 2) experimental autoimmune encephalomyelitis (EAE). Lesion size, leukocyte and soluble factor entry, neuronal death and demyelination were measured in both models, as well as clinical disability in EAE. To measure effects of JAM-A on astrocyte-lymphocyte binding and gene expression, we performed immunostaining and RNA sequencing on co-cultures of reactive astrocytes and CD3+ T-lymphocytes in the presence and absence of JAM-A. In CKO mice, cortical AdIL-1 lesions contained increased leukocyte numbers, but the location of most cells was restricted to the perivascular space, between the BBB and the GL, and overall lesion size and tissue pathology were reduced. In the EAE model, an increased proportion of CKO mice were resistant to disease, resulting in a decreased disability score compared with controls. In astrocyte-lymphocyte co-cultures, astrocytic JAM-A knock-down led to decreased astrocyte-lymphocyte binding. Collectively, these data suggest astrocytic expression of JAM-A promotes leukocyte migration and tissue damage during CNS inflammation, and clinical disability in an MS model.
Disclosure: Candice Chapouly: nothing to disclose
Abstract: P502
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 18 Neurobiology
Junctional Adhesion Molecule-A (JAM-A) is a versatile cell surface molecule involved in tight junction formation, leukocyte adhesion and signal transduction. During CNS inflammation, leukocytes must traverse the endothelial blood-brain barrier (BBB) and the astrocytic glial limitans (GL) in order to access the parenchyma and induce damage. Recently, we have found that reactive astrocytes at the GL upregulate JAM-A in vitro and in vivo. We hypothesized that astrocytic JAM-A mediates leukocyte adhesion and facilitates cell trafficking into the CNS parenchyma, and thus lesion pathogenesis and clinical disability. To selectively delete JAM-A from reactive astrocytes, we created a conditional JAM-A knock-out (CKO) mouse line by crossing mGFAP:Cre mice with JAM-Afl/fl mice. To test the importance of astrocytic JAM-A in CNS inflammatory lesion pathogenesis, we induced two models of CNS inflammatory disease in CKO mice and controls: 1) cortical injections of adenovirally mediated IL-1 (AdIL-1) and 2) experimental autoimmune encephalomyelitis (EAE). Lesion size, leukocyte and soluble factor entry, neuronal death and demyelination were measured in both models, as well as clinical disability in EAE. To measure effects of JAM-A on astrocyte-lymphocyte binding and gene expression, we performed immunostaining and RNA sequencing on co-cultures of reactive astrocytes and CD3+ T-lymphocytes in the presence and absence of JAM-A. In CKO mice, cortical AdIL-1 lesions contained increased leukocyte numbers, but the location of most cells was restricted to the perivascular space, between the BBB and the GL, and overall lesion size and tissue pathology were reduced. In the EAE model, an increased proportion of CKO mice were resistant to disease, resulting in a decreased disability score compared with controls. In astrocyte-lymphocyte co-cultures, astrocytic JAM-A knock-down led to decreased astrocyte-lymphocyte binding. Collectively, these data suggest astrocytic expression of JAM-A promotes leukocyte migration and tissue damage during CNS inflammation, and clinical disability in an MS model.
Disclosure: Candice Chapouly: nothing to disclose