Browsing by Author "Yates, Robin M"
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- ItemOpen AccessA role for cathepsin Z in neuroinflammation provides mechanistic support for an epigenetic risk factor in multiple sclerosis(2017-05-10) Allan, Euan R O; Campden, Rhiannon I; Ewanchuk, Benjamin W; Tailor, Pankaj; Balce, Dale R; McKenna, Neil T; Greene, Catherine J; Warren, Amy L; Reinheckel, Thomas; Yates, Robin MAbstract Background Hypomethylation of the cathepsin Z locus has been proposed as an epigenetic risk factor for multiple sclerosis (MS). Cathepsin Z is a unique lysosomal cysteine cathepsin expressed primarily by antigen presenting cells. While cathepsin Z expression has been associated with neuroinflammatory disorders, a role for cathepsin Z in mediating neuroinflammation has not been previously established. Methods Experimental autoimmune encephalomyelitis (EAE) was induced in both wildtype mice and mice deficient in cathepsin Z. The effects of cathepsin Z-deficiency on the processing and presentation of the autoantigen myelin oligodendrocyte glycoprotein, and on the production of IL-1β and IL-18 were determined in vitro from cells derived from wildtype and cathepsin Z-deficient mice. The effects of cathepsin Z-deficiency on CD4+ T cell activation, migration, and infiltration to the CNS were determined in vivo. Statistical analyses of parametric data were performed by one-way ANOVA followed by Tukey post-hoc tests, or by an unpaired Student’s t test. EAE clinical scoring was analyzed using the Mann–Whitney U test. Results We showed that mice deficient in cathepsin Z have reduced neuroinflammation and dramatically lowered circulating levels of IL-1β during EAE. Deficiency in cathepsin Z did not impact either the processing or the presentation of MOG, or MOG- specific CD4+ T cell activation and trafficking. Consistently, we found that cathepsin Z-deficiency reduced the efficiency of antigen presenting cells to secrete IL-1β, which in turn reduced the ability of mice to generate Th17 responses—critical steps in the pathogenesis of EAE and MS. Conclusion Together, these data support a novel role for cathepsin Z in the propagation of IL-1β-driven neuroinflammation.
- ItemOpen AccessDeriving Conventional Dendritic Cells from ER-Hoxb8 Immortalized Hematopoietic Stem and Progenitor Cells & Evaluating CD36 Dependent Uptake of Oxidized Low-Density Lipoprotein in Type 1 Conventional Dendritic Cells(2024-04-19) Moore, Melanie R; Canton, Johnathan Anias; Yates, Robin M; Jirik, Frank Robert; Ousman, Shalina S; Devinney, Rebekah PDendritic cells (DCs) play a crucial role in immunity, acting as professional antigen presenting cells (APCs) that bridge the innate and adaptive immune systems through antigen presentation. Among DC subtypes, type 1 conventional dendritic cells (cDC1s) excel in cross-presentation, which allows for the loading of processed antigen onto MHC I and is believed to be the primary means by which naïve CD8 T cells are converted into effector CD8 T cells. Despite comprising a small fraction of the total leukocyte population, cDC1s are disproportionately important in tumor environments, where their presence correlates with improved patient survival and treatment response across multiple cancers. However, studying cDCs poses challenges due to limited tools and inefficient methods for obtaining primary murine cDC1s. To address this, we developed a system that consistently provides high yields of cDCs, utilizing an easily accessible cell line of immortalized cDC progenitors. Using fluorescence activated cell sorting (FACS), we enriched an FLT3L-driven Hoxb8-immortalized hematopoietic stem and progenitor (HSPC) cell line to obtain a pre-cDC progenitor population. We then optimized existing methods of obtaining cDCs from bone marrow to consistently obtain cDC populations from our immortalized cDC progenitor cell line. Subsequently, we confirmed that this approach yields cDC subset compositions comparable to those obtained using established primary bone marrow protocols. Additionally, we investigated the role of CD36, a receptor for oxidized low-density lipoprotein (oxLDL), in cDC1s. We demonstrated a significant reduction in oxLDL uptake in cDCs lacking CD36, as well as in cDCs under the influence of macropinocytosis inhibiting drugs, suggesting that CD36-assisted macropinocytosis facilitates oxLDL uptake in cDC1s, ultimately leading to lipid body formation akin to macrophage foam cells. After replicating a commonly observed decrease in cross-presentation abilities in lipid-laden cDC1s, we provided a potential mechanism for this impairment, suggesting that a disruption in the recruitment of apolipoprotein 7c (APOL7C), which is vital to successful cross presentation, may be attributed to a significant oxLDL-dependent delay in phagosomal maturation. In summary, our research sheds light on the interplay between CD36, oxLDL, and cDC1s, offering valuable insights for future cDC studies and providing a promising tool for investigating their roles in immunity and disease.