Oxysterol Gradient Generation by Lymphoid Stromal Cells Guides Activated B Cell Movement during Humoral Responses

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
Immunity (Impact Factor: 21.56). 09/2012; 37(3):535–548. DOI: 10.1016/j.immuni.2012.06.015


7 alpha,25-dihydroxycholesterol (7 alpha,25-OHC) is a ligand for the G protein-coupled receptor EBI2; however, the cellular sources of this oxysterol are undefined. 7 alpha,25-OHC is synthesized from cholesterol by the stepwise actions of two enzymes, CH25H and CYP7B1, and is metabolized to a 3-oxo derivative by HSD3B7. We showed that all three enzymes control EBI2 ligand concentration in lymphoid tissues. Lymphoid stromal cells were the main CH25H- and CYP7B1-expressing cells required for positioning of B cells, and they also mediated 7 alpha,25-OHC inactivation. CH25H and CYP7B1 were abundant at the follicle perimeter, whereas CH25H expression by follicular dendritic cells was repressed. CYP7B1, CH25H, and HSD3B7 deficiencies each resulted in defective T cell-dependent plasma cell responses. These findings establish that CYP7B1 and HSD3B7, as well as CH25H, have essential roles in controlling oxysterol production in lymphoid tissues, and they suggest that differential enzyme expression in stromal cell subsets establishes 7 alpha,25-OHC gradients required for B cell responses.

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    • "Indeed Ch25h deficient mice normally regulate fatty acid and cholesterol metabolism [12]. Furthermore, immune cells such as macrophages [12] and stromal cells [13] are a rich source of Ch25h. Both 25-OHC and 7a,25-OHC are implicated in the immune response: 25-OHC suppresses IgA production by B cells [12] and has broad anti-viral properties [14] [15] while 7a,25-OHC guides B cell, dendritic cells and macrophages within the germinal follicules of the spleen and lymph nodes [13,16e18]. "
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    ABSTRACT: Perturbation of steroids pathways is linked to inflammation and chronic diseases, however the underlying mechanism remains unclear. Oxysterols, oxidized forms of cholesterol, are not only essential for bile synthesis and sterol transportation but have recently been shown to contribute to the immune response. In addition, serum oxysterols levels have been proposed as suitable candidate biomarkers for neurological diseases such as multiple sclerosis (MS). However how oxysterols modulate adaptive immunity is unknown and their functions in autoimmunity have not been investigated. The enzyme cholesterol 25 hydroxylase (Ch25h) is the rate limiting step to synthesize the oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC) from cholesterol. We here report, using the MS murine model experimental autoimmune encephalomyelitis (EAE), that Ch25h deletion significantly attenuated EAE disease course by limiting trafficking of pathogenic CD4+ T lymphocytes to the central nervous system (CNS). Mechanistically, we show a critical involvement for oxysterols in recruiting leukocytes into inflamed tissues and propose that 7α,25-OHC preferentially promotes the migration of activated CD44+CD4+ T cells by binding the G protein-coupled receptor called Epstein-Barr virus induced gene 2 (EBI2). Collectively, our results support a pro-inflammatory role for oxysterols during EAE and identify oxysterols as a potential therapeutic target to treat autoimmune diseases.
    Journal of Autoimmunity 11/2014; 56. DOI:10.1016/j.jaut.2014.10.001 · 8.41 Impact Factor
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    • "EBI2 expression has been well characterized for B cells, where differential expression of EBI2 during B cell maturation is a key regulator of B cell positioning in lymphoid follicles, collaborating with other B cell-expressed chemokine receptors including CXCR5 and CCR7 [24], [25], [30]. The migration of B cells is dictated by the oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC) [26], [27], [31], thereby ascribing EBI2 with a functional role as a chemotactic receptor. Moreover, EBI2 is required for positioning splenic CD4+ DC into bridging channels within germinal centers, which may promote sampling of systemic, particulate antigens [28], [29]. "
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    ABSTRACT: Epstein-Barr virus induced receptor 2 (EBI2), a Gαi-coupled G protein-coupled receptor, is a chemotactic receptor for B, T and dendritic cells (DC). Genetic studies have also implicated EBI2 as a regulator of an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) associated with autoimmune diseases, although the corollary in primary type I IFN-producing cells has not been reported. Here we demonstrate that EBI2 negatively regulates type I IFN responses in plasmacytoid DC (pDCs) and CD11b(+) myeloid cells. Activation of EBI2(-/-) pDCs and CD11b(+) cells with various TLR ligands induced elevated type I IFN production compared to wild-type cells. Moreover, in vivo challenge with endosomal TLR agonists or infection with lymphocytic choriomeningitis virus elicited more type I IFNs and proinflammatory cytokines in EBI2(-/-) mice compared to normal mice. Elevated systemic cytokines occurred despite impaired ability of EBI2-deficient pDCs and CD11b(+) cells to migrate from the blood to the spleen and peritoneal cavity under homeostatic conditions. As reported for other immune cells, pDC migration was dependent on the ligand for EBI2, 7α,25-dihydroxycholesterol. Consistent with a cell intrinsic role for EBI2, type I IFN-producing cells from EBI2-deficient mice expressed higher levels of IRF7 and IDIN genes. Together these data suggest a negative regulatory role for EBI2 in balancing TLR-mediated responses to foreign and to self nucleic acids that may precipitate autoimmunity.
    PLoS ONE 12/2013; 8(12):e83457. DOI:10.1371/journal.pone.0083457 · 3.23 Impact Factor
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    • "Moreover, recent studies reveal additional complexity. In­ deed, other cells of the microenvironment have been reported to express oxysterol­producing enzymes and to generate oxysterols (Diczfalusy et al., 2009; Yi et al., 2012). Because tumor microenvironment is a complex tissue, in which all the cells described so far to generate oxysterols are present (tumor cells, stromal cells, and immune cells), we speculate that appropriate mouse models are needed to investigate the rela­ tive contribution of oxysterol­producing cells within tumors. "
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    ABSTRACT: Tumor-infiltrating immune cells can be conditioned by molecules released within the microenvironment to thwart antitumor immune responses, thereby facilitating tumor growth. Among immune cells, neutrophils play an important protumorigenic role by favoring neoangiogenesis and/or by suppressing antitumor immune responses. Tumor-derived oxysterols have recently been shown to favor tumor growth by inhibiting dendritic cell migration toward lymphoid organs. We report that tumor-derived oxysterols recruit protumor neutrophils in a liver X receptor (LXR)-independent, CXCR2-dependent manner, thus favoring tumor growth by promoting neoangiogenesis and immunosuppression. We demonstrate that interfering with the oxysterol-CXCR2 axis delays tumor growth and prolongs the overall survival of tumor-bearing mice. These results identify an unanticipated protumor function of the oxysterol-CXCR2 axis and a possible target for cancer therapy.
    Journal of Experimental Medicine 07/2013; 210(9). DOI:10.1084/jem.20130440 · 12.52 Impact Factor
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