Abstract
BackgroundTight junctions (TJs) are membrane specializations characteristic of barrier-forming membranes, which function to seal the aqueous pathway between endothelial cells or epithelial cells and, thereby, obstruct intercellular solute and cellular movement. However, previous work from our laboratory found that claudin-5 (CLN-5), a TJ protein prominent at the blood–brain barrier (BBB), was also detected, ectopically, on leukocytes (CLN-5+) in the blood and central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a neuroinflammatory, demyelinating disease that is a model for multiple sclerosis. CLN-5 was further shown to be transferred from endothelial cells to circulating leukocytes during disease, prompting consideration this action is coupled to leukocyte transendothelial migration (TEM) into the CNS by fostering transient interactions between corresponding leukocyte and endothelial junctional proteins at the BBB.MethodsTo begin clarifying the significance of CLN-5+ leukocytes, flow cytometry was used to determine their appearance in the blood and CNS during EAE.ResultsFlow cytometric analysis revealed CLN-5+ populations among CD4 and CD8 T cells, B cells, monocytes and neutrophils, and these appeared with varying kinetics and to different extents in both blood and CNS. CLN-5 levels on circulating T cells further correlated highly with activation state. And, the percentage of CLN-5+ cells among each of the subtypes analyzed was considerably higher in CNS tissue than in blood, consistent with the interpretation that CLN-5+ leukocytes gain preferred access to the CNS.ConclusionSeveral leukocyte subtypes variably acquire CLN-5 in blood before they enter the CNS, an event that may represent a novel mechanism to guide leukocytes to sites for paracellular diapedesis across the BBB.
Highlights
Tight junctions (TJs) are membrane specializations that promote adhesion between both adjacent epithelial cells and endothelial cells
Appearance of CLN‐5+ leukocytes in blood and central nervous system (CNS) during EAE To get a sense of how disease progression was accompanied by appearance of CLN-5-bearing leukocytes, the total number of CD45+CLN-5+ cells in both blood and CNS compartments was determined, as was their percent representation in each tissue (Fig. 2)
The situation was reversed in the CNS, with the peak number C D45+CLN-5+ cells in the time course detected at D15 EAE
Summary
Tight junctions (TJs) are membrane specializations that promote adhesion between both adjacent epithelial cells and endothelial cells. Junctional adhesion molecules of intra-epithelial lymphocytes have been proposed to interact with their epithelial junctional protein neighbors in the small intestine [10] Supporting such an interactive role, our group [17] detected CLN-5-expressing (CLN-5+) leukocytes in blood and among perivascular infiltrates in spinal cord of mice with experimental autoimmune encephalomyelitis (EAE), a neuroinflammatory, demyelinating disease that serves as a model of multiple sclerosis (MS) [18]. As CLN-5 is a major TJ protein of the microvascular endothelium comprising the blood–brain barrier (BBB) and a crucial determinant of BBB status [20], these results could suggest CLN-5 appearance on leukocytes plays a key role in leukocyte TEM into the central nervous system (CNS) in the course of neuroinflammation In this regard, CLN-5+ leukocytes might serve a pioneering function, penetrating the TJs of the BBB earlier in the inflammatory process and, thereby, clearing the way for other leukocytes to follow. The percentage of CLN-5+ cells among each of the subtypes analyzed was considerably higher in CNS tissue than in blood, consistent with the interpretation that CLN-5+ leukocytes gain preferred access to the CNS
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