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  • To get an indication whether GBM derived

    2019-07-17

    To get an indication whether GBM-derived 25-OHC could act as a chemotactic signal for monocytes, lipid extracts of GM133 media were used in THP-1 migration assays. Although an indirect approach, these experiments revealed that medium lipid extracts induced monocyte migration in a quantitatively comparable manner as identical concentrations of exogenously added 25-OHC (Fig. 6). A question remaining is how 25-OHC contributes to monocyte attraction in the tumor environment. Association of secreted 25-OHC with lipoproteins would be a plausible explanation. In light of the facts that HDL particles transport 25-OHC in the circulation [47], shuttle oxysterols between the circulation and the leukotriene receptor antagonists [2] and are potent effectors of the monocytic migratory response [53] this hypothesis could be reasonable. Silva and colleagues [54] showed that an oxysterol-containing lipid fraction isolated from osteoblast-conditioned medium potently induces migration of human breast cancer cells, raising the possibility that oxysterols even contribute to metastasis. Results of the present study demonstrate that 25-OHC treatment of THP-1 monocytes induced vimentin intermediate filament reorganization to more cortical structures and a polarized phenotype (Fig. 5). Vimentin is the major intermediate filament protein present in leukocytes and plays an important role in leukocyte motility and endothelial diapedesis [55]. In line, vimentin intermediate filaments play a crucial role during adhesion molecule assembly that is needed during attachment and transendothelial migration [56], an event accompanying the recruitment of circulating monocytes across the tumor vasculature [57]. A characterization of human glioblastoma-associated macrophages revealed that besides lymphocytes and microglia, monocytes/macrophages represent the dominating inflammatory cell population infiltrating these tumors [58]. In summary, data obtained during the present study make it attractive to hypothesize that GBM-derived 25-OHC is able to recruit EBI2-expressing immune cells to the tumor environment. Thereby, 25-OHC may contribute to the recruitment of tumor-associated monocytes/macrophages that are potent modulators of gliomagenesis [59].
    Acknowledgments Financial support was provided by the Austrian Nationalbank (Anniversary Fund, project number 14534), the Austrian Research Promotion Agency (FFG; grant No. Bridge P820107), and the Austrian Science Fund (FWF; grant No. F3007, DK-W1241 and W1226, and P22521) and the National Institutes of Neurological Disease and Stroke (NS73831 to PSM). We thank David W. Russell, University of Texas Southwestern Medical Center, Dallas, Texas, USA, for the monoclonal antibody directed against cholesterol 25-hydroxylase.
    Introduction In order to mount a rapid and efficient antibody response, B cells undergo a series of dynamic movements within secondary lymphoid organs (Cyster, 2010). Naive B cells express the chemokine receptor CXCR5 and are attracted into follicles by this receptor’s ligand, CXCL13, which is made by stromal cells distributed throughout the follicle. After encountering antigen, activated B cells upregulate CCR7 and move within 6 hr leukotriene receptor antagonists to the B cell zone-T cell zone (B-T) boundary of the follicle in response to the T zone-expressed CCR7 ligand, CCL21. There, they interact with cognate T helper cells, and subsequently the T cell-primed B cells downregulate CCR7 and relocate to interfollicular and outer follicular regions for further clonal expansion prior to their differentiation into short-lived antibody-secreting plasma cells or germinal center (GC) B cells (Coffey et al., 2009; Cyster, 2010; Kerfoot et al., 2011; Kitano et al., 2011). EBI2, a G protein-coupled receptor, guides B cell movement along the B-T boundary and later to interfollicular and outer follicular regions (Gatto et al., 2009; Gatto et al., 2011; Kelly et al., 2011; Pereira et al., 2009). The absence of EBI2 from B cells results in their premature accumulation in the center of the follicle and diminished T cell-dependent plasma cell differentiation (Gatto et al., 2009; Pereira et al., 2009).