Abstract
Although JAM-C is abundantly expressed in the retinae and upregulated in choroidal neovascularization (CNV), it remains thus far poorly understood whether it plays a role in the blood-retinal barrier, which is critical to maintain the normal functions of the eye. Here, we report that JAM-C is highly expressed in retinal capillary endothelial cells (RCECs), and VEGF or PDGF-C treatment induced JAM-C translocation from the cytoplasm to the cytomembrane. Moreover, JAM-C knockdown in RCECs inhibited the adhesion and transmigration of macrophages from wet age-related macular degeneration (wAMD) patients to and through RCECs, whereas JAM-C overexpression in RCECs increased the adhesion and transmigration of macrophages from both wAMD patients and healthy controls. Importantly, the JAM-C overexpression-induced transmigration of macrophages from wAMD patients was abolished by the administration of the protein kinase C (PKC) inhibitor GF109203X. Of note, we found that the serum levels of soluble JAM-C were more than twofold higher in wAMD patients than in healthy controls. Mechanistically, we show that JAM-C overexpression or knockdown in RCECs decreased or increased cytosolic Ca2+ concentrations, respectively. Our findings suggest that the dynamic translocation of JAM-C induced by vasoactive molecules might be one of the mechanisms underlying inner endothelial BRB malfunction, and inhibition of JAM-C or PKC in RCECs may help maintain the normal function of the inner BRB. In addition, increased serum soluble JAM-C levels might serve as a molecular marker for wAMD, and modulating JAM-C activity may have potential therapeutic value for the treatment of BRB malfunction-related ocular diseases.
Highlights
A healthy blood-retinal barrier (BRB) serves to balance the circulation of molecules and to maintain a homeostatic environment for the normal function of the neural retina (Hudson and Campbell, 2019)
We found that junctional adhesion molecule (JAM)-C is expressed in retinal capillary endothelial cells (RCECs) and regulates the inner endothelial BRB function through its dynamic changes in cellular distribution
Increased JAM-C expression in human RCECs may lead to loss of retinal homeostasis by promoting macrophage infiltration, which can be inhibited by protein kinase C (PKC) inhibitor treatment
Summary
A healthy blood-retinal barrier (BRB) serves to balance the circulation of molecules and to maintain a homeostatic environment for the normal function of the neural retina (Hudson and Campbell, 2019). Three types of junction molecules have been identified in retinal cell junctions: tight junctions (TJs), adherens junctions, and gap junctions (Klaassen et al, 2013). These junctions are dynamic structures (Kowalczyk and Nanes, 2012; Solan and Lampe, 2018; Heinemann and Schuetz, 2019). TJs are the main junction type in both RCECs and RPECs contributing to BRB function (CunhaVaz et al, 2011). Their composition and architecture are quite different (Dejana, 2004). After the identification of TJ molecules, including zonula occludens (ZO) (Stevenson et al, 1986), occludin (Furuse et al, 1993), and claudins (Furuse et al, 1998), the junctional adhesion molecule (JAM) family was discovered, and their functions in TJ dynamics and leukocyte transmigration were elucidated (Garrido-Urbani et al, 2014)
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