Role of CD45 Signaling Pathway in Galactoxylomannan-Induced T Cell Damage

Previously, we reported that Galactoxylomannan (GalXM) activates the extrinsic and intrinsic apoptotic pathways through an interaction with the glycoreceptors on T cells. In this study we establish the role of the glycoreceptor CD45 in GalXM-induced T cell apoptosis, using CD45+/+ and CD45−/− cell lines, derived from BW5147 murine T cell lymphoma. Our results show that whereas CD45 expression is not required for GalXM association by the cells, it is essential for apoptosis induction. In CD45+/+ cells, CD45 triggering by GalXM reduces the activation of Lck, ZAP70 and Erk1/2. Conversely, in CD45−/− cells, Lck was hyperphosphorylated and did not show any modulation after GalXM stimulation. On the whole, our findings provide evidence that the negative regulation of Lck activation occurs via CD45 engagement. This appears to be related to the capacity of GalXM to antagonize T cell activation and induce T cell death. Overall this mechanism may be responsible for the immune paralysis that follows GalXM administration and could explain the powerful immunosuppression that accompanies cryptococcosis

Central role of the exchange factor GEF-H1 in TNF-α–induced sequential activation of Rac, ADAM17/TACE, and RhoA in tubular epithelial cells

Transactivation of the epidermal growth factor receptor (EGFR) by tumor necrosis factor-α (TNF-α) is a key step in mediating RhoA activation and cytoskeleton and junction remodeling in the tubular epithelium. In this study we explore the mechanisms underlying TNF-α–induced EGFR activation. We show that TNF-α stimulates the TNF-α convertase enzyme (TACE/a disintegrin and metalloproteinase-17), leading to activation of the EGFR/ERK pathway. TACE activation requires the mitogen-activated protein kinase p38, which is activated through the small GTPase Rac. TNF-α stimulates both Rac and RhoA through the guanine nucleotide exchange factor (GEF)-H1 but by different mechanisms. EGFR- and ERK-dependent phosphorylation at the T678 site of GEF-H1 is a prerequisite for RhoA activation only, whereas both Rac and RhoA activation require GEF-H1 phosphorylation on S885. Of interest, GEF-H1-mediated Rac activation is upstream from the TACE/EGFR/ERK pathway and regulates T678 phosphorylation. We also show that TNF-α enhances epithelial wound healing through TACE, ERK, and GEF-H1. Taken together, our findings can explain the mechanisms leading to hierarchical activation of Rac and RhoA by TNF-α through a single GEF. This mechanism could coordinate GEF functions and fine-tune Rac and RhoA activation in epithelial cells, thereby promoting complex functions such as sheet migration

Extravasation of leukocytes in comparison to tumor cells

The multi-step process of the emigration of cells from the blood stream through the vascular endothelium into the tissue has been termed extravasation. The extravasation of leukocytes is fairly well characterized down to the molecular level, and has been reviewed in several aspects. Comparatively little is known about the extravasation of tumor cells, which is part of the hematogenic metastasis formation. Although the steps of the process are basically the same in leukocytes and tumor cells, i.e. rolling, adhesion, transmigration (diapedesis), the molecules that are involved are different. A further important difference is that leukocyte interaction with the endothelium changes the endothelial integrity only temporarily, whereas tumor cell interaction leads to an irreversible damage of the endothelial architecture. Moreover, tumor cells utilize leukocytes for their extravasation as linkers to the endothelium. Thus, metastasis formation is indirectly susceptible to localization signals that are literally specific for the immune system. We herein compare the extravasation of leukocytes and tumor cells with regard to the involved receptors and the localization signals that direct the cells to certain organs and sites of the body

Molecular Basis of Cannabis-Induced Schizophrenia-Relevant Behaviours: Insights from Animal Models

Introduction: Cannabis use is a well-established component risk factor for schizophrenia; however, the mechanisms by which cannabis use increases schizophrenia risk are unclear. Animal models can elucidate mechanisms by which chronic cannabinoid treatment can induce schizophrenia-relevant neural changes, in a standardised manner often not possible using patient-based data. Methods: We review recent literature (within the past 10 years) using animal models of chronic and subchronic treatment with cannabinoids which target the cannabinoid 1 receptor [i.e. ∆9-tetrahydrocannabinol, CP55,940 and WIN55,212-2]. Schizophrenia-relevant behavioural consequences of chronic cannabinoid treatment are first briefly summarised, followed by a detailed account of changes to several receptor systems [e.g. cannabinoid, dopaminergic, glutamatergic, γ-aminobutyric acid (GABAe)rgic, serotonergic, noradrenergic], dendritic spine morphology and inflammatory markers following chronic cannabinoids. We distinguish between adolescent and adult cannabinoid treatments, to determine if adolescence is a period of susceptibility to schizophrenia-relevant molecular changes. Results: Chronic cannabinoid treatment induces behaviours relevant to positive, negative and cognitive symptoms of schizophrenia. Chronic cannabinoids also cause region- and subtype-specific changes to receptor systems (e.g. cannabinoid, dopaminergic, glutamatergic, GABAergic), as well as changes in dendritic spine morphology and upregulation of inflammatory markers. These changes often align with molecular changes observed in post-mortem tissue from schizophrenia patients and correspond with schizophrenia-relevant behavioural change in rodents. There is some indication that adolescence is a period of susceptibility to cannabinoid-induced schizophrenia-relevant neural change, but more research in this field is required to confirm this hypothesis. Conclusions: Animal models indicate several molecular mechanisms by which chronic cannabinoids contribute to schizophrenia-relevant neural and behavioural change. It is likely that a number of these mechanisms are simultaneously impacted by chronic cannabinoids, thereby increasing schizophrenia risk in individuals who use cannabis. Understanding how cannabinoids can affect several molecular targets provides critical insight into the complex relationship between cannabis use and schizophrenia risk