M‐sec regulates polarized secretion of inflammatory endothelial chemokines and facilitates CCL2‐mediated lymphocyte transendothelial migration

Identification of a novel inflammatory‐induced factor by which ECs promote polarized chemokine and cytokine secretion. Activation of endothelial cells by IL‐1β triggers the expression of multiple inflammatory cytokines and leukocyte‐attracting chemokines. The machineries involved in the secretion of these inducible proteins are poorly understood. With the use of genome‐wide transcriptional analysis of inflamed human dermal microvascular endothelial cells, we identified several IL‐1β−induced candidate regulators of these machineries and chose to focus our study on TNF‐α‐induced protein 2 (myeloid‐secretory). The silencing of myeloid‐secretory did not affect the ability of inflamed endothelial cells to support the adhesion and crawling of effector T lymphocytes. However, the ability of these lymphocytes to complete transendothelial migration across myeloid‐secretory‐silenced human dermal microvascular endothelial cells was inhibited significantly. These observed effects on lymphocyte transendothelial migration were recovered completely when exogenous promigratory chemokine CXCL12 was overlaid on the endothelial barrier. A polarized secretion assay suggested that the silencing of endothelial myeloid‐secretory impairs T effector transendothelial migration by reducing the preferential secretion of endothelial‐produced CCL2, a key transendothelial migration‐promoting chemokine for these lymphocytes, into the basolateral endothelial compartment. Myeloid‐secretory silencing also impaired the preferential secretion of other endothelial‐produced inflammatory chemokines, as well as cytokines, such as IL‐6 and GM‐CSF, into the basolateral endothelial compartment. This is the first evidence of a novel inflammation‐inducible machinery that regulates polarized secretion of endothelial CCL2 and other inflammatory chemokines and cytokines into basolateral endothelial compartments and facilitates the ability of endothelial CCL2 to promote T cell transendothelial migration.