Activated leukocyte cell adhesion molecule on human oligodendrocytes mediates Th17 cell adhesion
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PROVIDER: PRJNA962726 | 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.
2023-08-31 | GSE230828 | GEO
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2019-01-28 | PXD008973 | Pride
Project description:Impaired regulatory T cell-dendritic cell interactions contribute to autoimmunity in leukocyte adhesion deficiency type-1
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Project description:T helper (Th)17 cells are considered to contribute to inflammatory mechanisms in diseases such as multiple sclerosis (MS). However, the discussion persists regarding their true role in patients. Here, we visualized central nervous system (CNS) inflammatory processes in models of MS live in vivo and in MS brains and discovered that CNS-infiltrating Th17 cells form prolonged stable contact with oligodendrocytes. Strikingly, compared to Th2 cells, direct contact with Th17 worsened experimental demyelination, caused damage to human oligodendrocyte processes and increased cell death. Importantly, we found that in comparison to Th2 cells, both human and murine Th17 cells express higher levels of the integrin CD29, which is linked to glutamate release pathways. Of note, contact of human Th17 cells with oligodendrocytes triggered release of glutamate. As we found that Th17-polarized cells release glutamate in contact with oligodendrocytic cells, we then assessed the impact of glutamate itself on human oligodendrocytes in primary culture. We found that 12-24h application of glutamate - but not pro-inflammatory cytokines TNFα or IFN-γ - strongly decreased the area and complexity of human oligodendrocyte processes in vitro without affecting oligodendrocyte survival. To further investigate the impact of glutamate on human oligodendrocytes we used single cell RNA sequencing (scRNAseq) of the human oligodendrocytes in primary culture, unstimulated (vehicle) and stimulated with glutamate. Following exposure to glutamate we observed induced cell stress and changes in biosynthesis of cholesterol and lipids in mature human oligodendrocytes. Finally, exposure to glutamate decreased myelination whereas blockade of CD29 preserved oligodendrocyte processes from Th17-mediated injury. Our data provide first evidence for direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for new therapeutic opportunities in MS.
2021-07-25 | GSE180670 | GEO
Project description:Restricted expression of activated leukocyte cell adhesion molecule (ALCAM) by hematopoietic cells suggests an important role in the immune system and hematopoiesis. To get insight into the mechanisms that control ALCAM-mediated adhesion we have investigated homotypic ALCAM-ALCAM interactions. Here, we demonstrate that the cytoskeleton regulates ALCAM-mediated cell adhesion because inhibition of actin polymerization by cytochalasin D (CytD) strongly induces homotypic ALCAM-ALCAM interactions. This induction of cell adhesion is likely due to clustering of ALCAM at the cell surface, which is observed after CytD treatment. Single-particle tracking demonstrated that the lateral mobility of ALCAM in the cell membrane is increased 30-fold after CytD treatment. In contrast, both surface distribution and adhesion of a glycosylphosphatidylinositol (GPI)-anchored ALCAM mutant are insensitive to CytD, despite the increase in lateral mobility of GPI-ALCAM upon CytD treatment. This demonstrates that clustering of ALCAM is essential for cell adhesion, whereas enhanced diffusion of ALCAM alone is not sufficient for cluster formation. In addition, upon ligand binding, both free diffusion and the freely dragged distance of wild-type ALCAM, but not of GPI-ALCAM, are reduced over time, suggesting strengthening of the cytoskeleton linkage. From these findings we conclude that activation of ALCAM-mediated adhesion is dynamically regulated through actin cytoskeleton-dependent clustering.
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Project description:Cell adhesion plays an important role in determining cell shape and function in a variety of physiological and pathophysiological conditions. While links between metabolism and cell adhesion were previously suggested, the exact context and molecular details of such a cross-talk remain incompletely understood. Our study shows that PGC-1alpha, a pivotal transcriptional co-activator of metabolic gene expression, acts to inhibit expression of cell adhesion genes. Using cell lines as well as primary cells, we show that both endogenous and exogenous PGC-1a down-regulate expression of a variety of cell adhesion molecules.
2017-01-17 | GSE81171 | GEO
Project description:Activated leukocyte cell adhesion molecule (ALCAM) has been implicated in tumorigenesis. Our goal was to examine the levels of ALCAM, in addition to the classical breast cancer tumor markers carbohydrate antigen 15-3 (CA15-3) and carcinoembryonic antigen (CEA), in serum by quantitative enzyme-linked immunosorbent assay for diagnosis in breast cancer patients. The 3 proteins were measured in serum of 100 healthy women, 50 healthy men and 150 breast carcinoma patients. The diagnostic sensitivity and specificity of the tests were calculated and the association of serum marker concentrations with various clinicopathologic variables was examined using nonparametric Kruskal-Wallis tests. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of the biomarkers. ALCAM, with area under the curve (AUC) of 0.78 [95% CI: 0.73, 0.84] outperformed CA15-3 (AUC = 0.70 [95% CI: 0.64, 0.76]) and CEA (AUC= 0.63 [95% CI: 0.56, 0.70]). The incremental values of AUC for ALCAM over that for CA15-3 were statistically significant (Delong test, p < 0.05). Combining CA15-3 and ALCAM yielded a ROC curve with an AUC of 0.81 (95% CI [0.75, 0.87]). Serum ALCAM appears to be a new biomarker for breast cancer and may have value for disease diagnosis.
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Project description:From a differential mRNA display comparing a non- and a highly metastasizing human melanoma cell line, we isolated and characterized memD. memD is preferentially expressed in the highly metastasizing melanoma cell lines of a larger panel. The encoded protein, MEMD, is identical to activated leukocyte cell adhesion molecule (ALCAM), a recently identified ligand of CD6. ALCAM is involved in homophylic (ALCAM-ALCAM) and heterophylic (ALCAM-CD6) cell adhesion interactions. We have studied MEMD/ALCAM cell-cell interactions between human melanoma cells. The expression of this cell adhesion molecule not only correlates with enhanced metastatic properties and with aggregational behavior of human melanoma cells as tested by FACS analysis, but transfection experiments also make clear that MEMD/ALCAM expression is essential for cell-cell interaction of the investigated human melanoma cells. As the melanoma cell lines analyzed are all CD6 negative, these results strongly suggest that MEMD/ALCAM is an adhesion molecule mediating homophylic clustering of melanoma cells. MEMD/ALCAM expression is not restricted to subsets of leukocytes and melanoma cells, it can also be found in healthy organs and in several other malignant tumor cell lines. Besides, MEMD/ALCAM is also expressed in cultured endothelial cells, pericytes and melanocytes, in xenografts derived from the radial and vertical growth phase and in 4 of 13 melanoma metastasis lesions. The potential role is discussed of MEMD/ALCAM mediated cell-cell interactions in migration of mobile cells (ie, activated leukocytes, metastasizing tumor cells) through tissues.
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Project description:T helper 17 (Th17) cells are a distinct subset of CD4+ T cells necessary for maintaining gut homeostasis and have prominent roles in autoimmunity and inflammation. Th17 cells have unique metabolic features, including a stem cell-like signature and reliance on mitochondrial respiratory chain function and tricarboxylic acid (TCA) cycle to coordinate metabolic and epigenetic remodeling. Dynamic changes in mitochondrial membrane morphology are key to sustain organelle function. However, it remains unclear whether mitochondrial membrane remodeling orchestrates metabolic and differentiation events in Th17 cells. Here we demonstrate that mitochondrial membrane fusion and tight cristae organization are required for Th17 cell function (i.e. cytokine expression). As a genetic model system we employ Th17 specific deletion of optic atrophy 1 (OPA1), a gene that encodes a protein involved in mitochondrial inner membrane fusion and cristae organization. As a result, we find that Th17 cells rely on mitochondrial fusion (due to their low metabolic activity). Here, we carry out DIA-based differential quantitative proteomic analysis of murine wild-type and OPA1 knock-out Th17 cells. Through Ingenuity pathway analysis and together with transcriptional and metabolomic profiling we identify the serine/threonine kinase liver associated kinase B1 (LKB1/STK11) as an essential node coupling mitochondrial function to IL-17A cytokine expression in T cells.
2022-10-13 | PXD036162 | Pride
Project description:BACKGROUND:Cell adhesion molecules are plasma membrane proteins specialized in cell-cell recognition and adhesion. Two related adhesion molecules, Necl-1 and Necl-2/SynCAM, were recently described and shown to fulfill important functions in the central nervous system. The purpose of the work was to investigate the distribution, and the properties of Necl-3/SynCAM-2, a previously uncharacterized member of the Necl family with which it shares a conserved modular organization and extensive sequence homology. RESULTS:We show that Necl-3/SynCAM-2 is a plasma membrane protein that accumulates in several tissues, including those of the central and peripheral nervous system. There, Necl-3/SynCAM-2 is expressed in ependymal cells and in myelinated axons, and sits at the interface between the axon shaft and the myelin sheath. Several independent assays demonstrate that Necl-3/SynCAM-2 functionally and selectively interacts with oligodendrocytes. We finally prove that Necl-3/SynCAM-2 is a bona fide adhesion molecule that engages in homo- and heterophilic interactions with the other Necl family members, leading to cell aggregation. CONCLUSION:Collectively, our manuscripts and the works on Necl-1 and SynCAM/Necl-2 reveal a complex set of interactions engaged in by the Necl proteins in the nervous system. Our work also support the notion that the family of Necl proteins fulfils key adhesion and recognition functions in the nervous system, in particular between different cell types.
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