Impaired regulatory T cell-dendritic cell interactions contribute to autoimmunity in leukocyte adhesion deficiency type-1
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PROVIDER: PRJNA890610 | ENA |
REPOSITORIES: ENA
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Project description:Multiple sclerosis is a chronic neuroinflammatory disorder characterized by demyelination, oligodendrocyte damage/loss and neuroaxonal injury in the context of immune cell infiltration in the central nervous system. No neuroprotective therapy is available to promote the survival of oligodendrocytes and protect their myelin processes in immune-mediated demyelinating diseases. Pro-inflammatory CD4 T helper (Th)17 cells can directly interact with oligodendrocytes in multiple sclerosis and its animal model, causing injury to myelinating processes and cell death through direct contact. However, the molecular mechanisms underlying the close contact and subsequent detrimental interaction of Th17 cells with oligodendrocytes remain unclear. In this study we conducted single cell RNA sequencing of human primary oligodendrocytes cultured alone, in contact or separated by an insert with primary Th17 polarized T cells and identified several cell adhesion molecules that may modulate T cell contact mediated damage of oligodendrocytes. Furthermore, we used flow cytometry and immunofluorescence studies on central nervous system tissue from multiple sclerosis subjects, its animal model and controls to characterize the expression of cell adhesion molecules by mature oligodendrocytes. We found that a significant proportion of human and murine mature oligodendrocytes express melanoma cell adhesion molecule and activated leukocyte cell adhesion molecule in multiple sclerosis, EAE and controls although their regulation differ between human and mouse. We observed that exposure to pro-inflammatory cytokines or to human activated T cells are associated with a marked downregulation of the expression of melanoma cell adhesion molecule but not activated leukocyte cell adhesion molecule at the surface of human primary oligodendrocytes. Furthermore, we used in vitro live-imaging, immunofluorescence, and flow cytometry to determine the contribution of these molecules to Th17-polarized cell adhesion and cytotoxicity towards human oligodendrocytes. Silencing and blocking activated leukocyte cell adhesion molecule but not melanoma cell adhesion molecule limited prolonged interactions between oligodendrocytes and Th17-polarized cells, resulting in decreased adhesion of Th17-polarized cells to oligodendrocytes and conferred significant protection of oligodendrocytic processes.
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Project description:Tumor cell extravasation takes place, similar to leukocytes, in a multi-step process by which cells emigrate from the blood stream through the vascular endothelium into the tissue. Selectins are regarded as the most important molecules for the first capturing step of the cascade. Whether all tumor cells employ selectin dependent adhesion to metastasize or there is an alternative mechanism still is an open question. Comparative transcriptomic analysis of OVCAR8 and SKOV3 cultured cells and revealed that one third of genes encoding proteins involved in the selectin dependent leukocyte like adhesion cascade show lower expression levels in OVCAR8 cultured cells in comparison to that in SKOV3 cultured cells. In contrast to SKOV3 cells, c-Fos overexpression in OVCAR8 cells does not significantly influence expression of the leukocyte like adhesion cascade genes leaving them at similar levels as in control OVCAR8 cells. The intraperitoneal xenograft model of OVCAR8 cells demonstrated that aggressiveness of OVCAR8-derived tumors is not dependent of c-Fos expression level and comparable with that for SKOV3 control tumors. Based on transcriptome array data we analyzed in details expression of genes encoding proteins involved in the leukocyte like adhesion cascade, E- and P-selectin ligands, as well as glycosylation enzymes in both type of tumors. Our results suggest that selectin-dependent mechanism is not the only for adhesion of OVCAR8 ovarian cancer cells. There is at least one additional mechanism of extravasation that does not rely on selectins.
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Project description:The adhesion of monocytic cells to the M-^SdysfunctionalM-^T endothelium constitutes a critical step in the initiation of atherosclerotic plaque formation. Cigarette smoke (CS) has been shown to contribute to the monocyte-endothelial adhesion process. Yet, the complex mechanisms underlying this event remain to be discovered. In the systemic compartment, monocytes and endothelial cells are exposed primarily to soluble constituents originating from the inhaled CS and absorbed through the lung alveolar epithelium and the adjacent microvascular endothelium. Considering this rationale, we developed an in vitro adhesion assay, intending to mimic the in vivo situation, to deeply investigate the impact of CS on the adhesion of monocytic cell to the endothelium. Using a transcriptomics approach followed by confirmation experiments, we were able to identify a key mechanism by which aqueous extract of CS (smoke-bubbled Phosphate Buffered Saline, sbPBS) promotes the adhesion of monocytic Mono Mac 6 (MM6) cells to the human umbilical vein endothelial cells (HUVECs). While CS-derived constituents directly provoke a strong oxidative stress response in both cell types, the induced expression of E-selectin, VCAM-1 and ICAM-1 adhesion molecules, responsible for the binding of MM6 cells to HUVECs, occurs through a proinflammatory paracrine effect. We demonstrate that this effect is mainly driven by TNF? produced by MM6 cells exposed to sbPBS. In conclusion, the development of our in vitro adhesion assay, intending to mimic the in vivo conditions, enabled to show that the adhesion of monocytic cells to endothelial cells is promoted through an indirect effect of the sbPBS.
2014-04-24 | E-MTAB-1173 | biostudies-arrayexpress
Project description:The nervous and immune systems are intricately linked. Although psychological stress is known to affect immune function, direct mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood. Here, we show that distinct brain regions shape leukocyte distribution throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that the motor cortex induces rapid neutrophil mobilization to peripheral tissues via skeletal muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow via direct and cell-intrinsic glucocorticoid signaling. These stress-induced counter-directional and population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and precipitating their recruitment to atherosclerotic plaques. On the other hand, stress-induced leukocyte shifts impair adaptive immunity, increasing susceptibility to SARS-Cov-2 and influenza infection but protecting against autoimmunity in a model of multiple sclerosis. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, thus calibrating the immune system’s capacity to respond to physical threats.
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Project description:The exit of antigen-presenting cells (APC) and lymphocytes from inflamed skin to afferent lymph is vital for the initiation and maintenance of dermal immune responses. How such exit is achieved and how cells transmigrate the distinct endothelium of lymphatic vessels is however unknown. Here we show that inflammatory cytokines trigger activation of dermal lymphatic endothelial cells (LEC) leading to expression of the key leukocyte adhesion receptors ICAM-1, VCAM-1 and E-selectin, as well as a discrete panel of chemokines and other potential regulators of leukocyte transmigration. Furthermore, we show that both ICAM-1 and VCAM-1 are induced in the dermal lymphatic vessels of mice exposed to skin contact hypersensitivity where they mediate lymph node trafficking of DC via afferent lymphatics. Lastly, we show that TNF_-stimulates both DC adhesion and transmigration of dermal LEC monolayers in vitro and that the process is efficiently inhibited by ICAM-1 and VCAM-1 adhesion-blocking mAbs. These results reveal a CAM-mediated mechanism for recruiting leukocytes to the lymph nodes in inflammation and highlight the process of lymphatic transmigration as a potential new target for anti-inflammatory therapy. Keywords: TNFalpha, Lymphatic endothelium, induction, Inflammation
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Project description:A Whole-Cell Screening Platform for Discovering Cell Adhesion Molecules Enabling Programmable Bacterial Cell-Cell Adhesion
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