Activation of Annexin <scp>A2</scp> signaling at the blood–brain barrier in a mouse model of multiple sclerosis

<jats:title>Abstract</jats:title><jats:sec><jats:label /><jats:p>Blood–brain barrier (BBB) dysfunction is a fundamental cause of multiple sclerosis and identifying the molecules that are responsible is an urgent matter. Protein expression was comprehensively quantified at the BBB of experimental autoimmune encephalomyelitis (EAE) mice, a model of multiple sclerosis, using the SWATH method. Concerning tight junction molecules, the level of expression of Claudin‐5, which, in a previous immunohistochemical analysis, was confirmed to be down‐regulated by EAE, remained unchanged, but the expression of Claudin‐11 and Occludin was decreased by 0.69‐ and 0.62‐fold, respectively, in brain capillaries isolated from EAE mice. A number of other cell–cell junctional molecules including ESAM, CADM1, CADM2, CADM3, CADM4, and HEPACAM were also down‐regulated. The levels of expression of intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1), which directly mediate the infiltration of lymphocytes across the BBB, were increased in EAE mice by 3.3‐ and 2.6‐fold, respectively. The expression of CXADR, which possibly facilitates the adhesion of migrating cells, was also increased by 3.5‐fold. Interestingly, various members of the Annexin A (ANXA) family were also up‐regulated in brain capillaries that were isolated from EAE mice. In a pathway associated with cell infiltration and tight junction disruption, a series of molecules that are involved in ANXA2 signaling (ANXA2, PTP1B, Ahnak, S100A11, CD44, Kindlin2, Integrin α5, Fibronectin, Fibrinogen) were up‐regulated. ANXA2 is selectively and abundantly expressed in endothelial cells in the brain. The daily administration of an ANXA2 inhibitor (LCKLSL peptide) significantly suppressed the development of EAE in mice. In summary, the activation of ANXA2 signaling at the BBB appear to play an important role in the pathogenesis of EAE.</jats:p></jats:sec><jats:sec><jats:label /><jats:p> <jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/jnc15578-fig-0007-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text> </jats:p></jats:sec>