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Impaired macrophage trafficking and increased helper T-cell recruitment with loss of cadherin-11 in atherosclerotic immune response


Johnson CLCamryn L , Riley LLance , Bersi MMatthew , Linton MFMacRae F , Merryman WDW David . American journal of physiology. Heart and circulatory physiology. 2021 9 10; 321(4). H756-H769


Inflammation caused by infiltrating macrophages and T cells promotes plaque growth in atherosclerosis. Cadherin-11 (CDH11) is a cell-cell adhesion protein implicated in several fibrotic and inflammatory diseases. Much of the research on CDH11 concerns its role in fibroblasts, although its expression in immune cells has been noted as well. The objective of this study was to assess the effect of CDH11 on the atherosclerotic immune response. In vivo studies of atherosclerosis indicated an increase in in plaque tissue. However, global loss of resulted in increased atherosclerosis and inflammation. It also altered the immune response in circulating leukocytes, decreasing myeloid cell populations and increasing T-cell populations, suggesting possible impaired myeloid migration. Bone marrow transplants from -deficient mice resulted in similar immune cell profiles. In vitro examination of macrophages revealed reduced migration, despite upregulation of a number of genes related to locomotion. Flow cytometry revealed an increase in CD3 and CD4 helper T-cell populations in the blood of both the global loss and the bone marrow transplant animals, possibly resulting from increased expression by macrophages of major histocompatibility complex class II molecule genes, which bind to CD4 T cells for coordinated activation. CDH11 fundamentally alters the immune response in atherosclerosis, resulting in part from impaired macrophage migration and altered macrophage-induced T-cell activation. Cadherin-11 is well known to contribute to inflammatory and fibrotic disease. Here, we examined its role in atherosclerosis progression, which is predominantly an inflammatory process. We found that while cadherin-11 is associated with plaque progression, global loss of cadherin-11 exacerbated the disease phenotype. Moreover, loss of cadherin-11 in bone marrow-derived immune cells resulted in impaired macrophage migration and an unexplained increase in circulating helper T cells, presumably due to altered macrophage function without cadherin-11.