Abstract:The adhesion molecule L1, which is extensively characterized in the nervous
system, is also expressed in dendritic cells (DCs), but its function there has
remained elusive. To address this issue, we ablated L1 expression in DCs of
conditional knockout mice. L1-deficient DCs were impaired in adhesion to and
transmigration through monolayers of either lymphatic or blood vessel
endothelial cells, implicating L1 in transendothelial migration of DCs. In
agreement with these findings, L1 was expressed in cutaneous D… Show more
“…To investigate whether direct interaction was required for Ca signals, LECs were grown to confluency, and DCs were layered on top. In this setting, DCs effectively transmigrated the monolayer (Maddaluno et al., 2009) as revealed by phase contrast live cell imaging (Figure 4C; Movie S4). Transmigration was dependent on the secretion of CCL21, as non-infected or CCL21ΔN-mCherry-infected LECs were only occasionally penetrated by DCs (Figure S2D; Movie S4).…”
Section: Resultsmentioning
confidence: 99%
“…At sites of intravasated β2 deficient ( Itgb2 −/− ) DCs, CCL21 depots were dispersed from Golgi similar to wild-type DC samples (Figures S2E and S2F). Thus, other molecular interactions at the DC-LEC interface, such as the plexin1A-semaphorin3A axis (Takamatsu et al., 2010), L1 (Maddaluno et al., 2009), or yet unidentified factors might trigger the signal.Figure 4Endothelial Ca Signaling Facilitates DC Transmigration In Vitro(A) Transmission electron micrograph at a site of DC-LEC interaction at ear dermis lymphatic capillary. Black line indicates thinning of endothelial cell at site of interaction.…”
SummaryTrafficking cells frequently transmigrate through epithelial and endothelial monolayers. How monolayers cooperate with the penetrating cells to support their transit is poorly understood. We studied dendritic cell (DC) entry into lymphatic capillaries as a model system for transendothelial migration. We find that the chemokine CCL21, which is the decisive guidance cue for intravasation, mainly localizes in the trans-Golgi network and intracellular vesicles of lymphatic endothelial cells. Upon DC transmigration, these Golgi deposits disperse and CCL21 becomes extracellularly enriched at the sites of endothelial cell-cell junctions. When we reconstitute the transmigration process in vitro, we find that secretion of CCL21-positive vesicles is triggered by a DC contact-induced calcium signal, and selective calcium chelation in lymphatic endothelium attenuates transmigration. Altogether, our data demonstrate a chemokine-mediated feedback between DCs and lymphatic endothelium, which facilitates transendothelial migration.
“…To investigate whether direct interaction was required for Ca signals, LECs were grown to confluency, and DCs were layered on top. In this setting, DCs effectively transmigrated the monolayer (Maddaluno et al., 2009) as revealed by phase contrast live cell imaging (Figure 4C; Movie S4). Transmigration was dependent on the secretion of CCL21, as non-infected or CCL21ΔN-mCherry-infected LECs were only occasionally penetrated by DCs (Figure S2D; Movie S4).…”
Section: Resultsmentioning
confidence: 99%
“…At sites of intravasated β2 deficient ( Itgb2 −/− ) DCs, CCL21 depots were dispersed from Golgi similar to wild-type DC samples (Figures S2E and S2F). Thus, other molecular interactions at the DC-LEC interface, such as the plexin1A-semaphorin3A axis (Takamatsu et al., 2010), L1 (Maddaluno et al., 2009), or yet unidentified factors might trigger the signal.Figure 4Endothelial Ca Signaling Facilitates DC Transmigration In Vitro(A) Transmission electron micrograph at a site of DC-LEC interaction at ear dermis lymphatic capillary. Black line indicates thinning of endothelial cell at site of interaction.…”
SummaryTrafficking cells frequently transmigrate through epithelial and endothelial monolayers. How monolayers cooperate with the penetrating cells to support their transit is poorly understood. We studied dendritic cell (DC) entry into lymphatic capillaries as a model system for transendothelial migration. We find that the chemokine CCL21, which is the decisive guidance cue for intravasation, mainly localizes in the trans-Golgi network and intracellular vesicles of lymphatic endothelial cells. Upon DC transmigration, these Golgi deposits disperse and CCL21 becomes extracellularly enriched at the sites of endothelial cell-cell junctions. When we reconstitute the transmigration process in vitro, we find that secretion of CCL21-positive vesicles is triggered by a DC contact-induced calcium signal, and selective calcium chelation in lymphatic endothelium attenuates transmigration. Altogether, our data demonstrate a chemokine-mediated feedback between DCs and lymphatic endothelium, which facilitates transendothelial migration.
“…The adhesion molecule L1, found on glia and extensively characterized in the nervous system (Dahme et al 1997; Kenwrick et al 2000), is also expressed in cells of myeloid origin such as DCs (Maddaluno et al 2009; Pancook et al 1997), but its function there has remained elusive. To address this issue, L1CAM expression was ablated in DCs of conditional knockout mice.…”
Section: Firm Adhesionmentioning
confidence: 99%
“…To address this issue, L1CAM expression was ablated in DCs of conditional knockout mice. L1CAM-deficient DCs were impaired in adhesion to and transmigration through monolayers of either lymphatic or blood vessel endothelial cells, implicating L1CAM in transendothelial migration of DCs (Maddaluno et al 2009) The interaction of L1CAM with homophilic and heterophilic receptors on brain microvasculature has yet to be examined.…”
Although the central nervous system (CNS) is considered to be an immunoprivileged site, it is susceptible to a host of autoimmune as well as neuroinflammatory disorders owing to recruitment of immune cells across the blood–brain barrier into perivascular and parenchymal spaces. Dendritic cells (DCs), which are involved in both primary and secondary immune responses, are the most potent immune cells in terms of antigen uptake and processing as well as presentation to T cells. In light of the emerging importance of DC traficking into the CNS, these cells represent good candidates for targeted immunotherapy against various neuroinflammatory diseases. This review focuses on potential physiological events and receptor interactions between DCs and the microvascular endothelial cells of the brain as they transmigrate into the CNS during degeneration and injury. A clear understanding of the underlying mechanisms involved in DC migration may advance the development of new therapies that manipulate these mechanistic properties via pharmacologic intervention. Furthermore, therapeutic validation should be in concurrence with the molecular imaging techniques that can detect migration of these cells in vivo. Since the use of noninvasive methods to image migration of DCs into CNS has barely been explored, we highlighted potential molecular imaging techniques to achieve this goal. Overall, information provided will bring this important leukocyte population to the forefront as key players in the immune cascade in the light of the emerging contribution of DCs to CNS health and disease.
“…L1 is dysregulated in some tumours and is for instance involved in chemoresistance in ovarian cancer cells. Unexpectedly, L1 was found to be aberrantly expressed in cancer and inflammatory vasculature [51] and its expression was induced by pro-angiogenic and inflammatory cytokines.…”
Section: Session 4: More Types Of Cancer and Selected Presentationsmentioning
The Fourth Metronomic and Anti-angiogenic Therapy Meeting was held in Milan 24–25 June 2014. The meeting was a true translational meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on metronomic approaches. Several speakers emphasised that exact mechanisms of action, best timing, and optimal dosage are still not well understood and that the field would learn a lot from ancillary studies performed during the clinical trials of metronomic chemotherapies. From the pre-clinical side, new research findings indicate additional possible mechanisms of actions of metronomic schedule on the immune and blood vessel compartments of the tumour micro-environment. New clinical results of metronomic chemotherapy were presented in particular in paediatric cancers [especially neuroblastoma and central nervous system (CNS) tumours], in angiosarcoma (together with beta-blockers), in hepatocellular carcinoma, in prostate cancer, and in breast cancer. The use of repurposed drugs such as metformin, celecoxib, or valproic acid in the metronomic regimen was reported and highlighted the potential of other candidate drugs to be repurposed. The clinical experiences from low- and middle-income countries with affordable regimens gave very encouraging results which will allow more patients to be effectively treated in economies where new drugs are not accessible. Looking at the impact of metronomic approaches that have been shown to be effective, it was admitted that those approaches were rarely used in clinical practice, in part because of the absence of commercial interest for companies. However, performing well-designed clinical trials of metronomic and repurposing approaches demonstrating substantial improvement, especially in populations with the greatest unmet needs, may be an easier solution than addressing the financial issue. Metronomics should always be seen as a chance to come up with new innovative affordable approaches and not as a cheap rescue strategy.
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