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

Yi, Tangsheng; Wang, Xiaoming; Kelly, Lisa M.; An, Jinping; Xu, Ying; Sailer, Andreas W.; Gustafsson, Jan Åke; Russell, David W.; Cyster, Jason G.

doi:10.1016/j.immuni.2012.06.015

Cited by 187 publications

(234 citation statements)

References 38 publications

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“…These results along with the observations that neutrophils are found close to cells of transformed islets overexpressing Cyp46a1 and that 24S-HC was shown to induce neutrophil migration in vitro (14) reinforce the idea that 24S-HC oxysterol might be crucially involved in vivo in the positioning of proangiogenic neutrophils in the proximity of cells releasing high amounts of 24S-HC. The concept that oxysterols may behave as short-range chemoattractants has recently been described for the oxysterol 7α, 25-HC, which controls cell positioning within specific areas of lymphoid organs (39). The positioning role of 24S-HC in physiologic conditions deserves further investigations.…”

Section: Discussionmentioning

confidence: 99%

24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development

Soncini

Corna

Moresco

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cells in the tumor microenvironment may be reprogrammed by tumor-derived metabolites. Cholesterol-oxidized products, namely oxysterols, have been shown to favor tumor growth directly by promoting tumor cell growth and indirectly by dampening antitumor immune responses. However, the cellular and molecular mechanisms governing oxysterol generation within tumor microenvironments remain elusive. We recently showed that tumorderived oxysterols recruit neutrophils endowed with protumoral activities, such as neoangiogenesis. Here, we show that hypoxia inducible factor-1a (HIF-1α) controls the overexpression of the enzyme Cyp46a1, which generates the oxysterol 24-hydroxycholesterol (24S-HC) in a pancreatic neuroendocrine tumor (pNET) model commonly used to study neoangiogenesis. The activation of the HIF-1α-24S-HC axis ultimately leads to the induction of the angiogenic switch through the positioning of proangiogenic neutrophils in proximity to Cyp46a1 + islets. Pharmacologic blockade or genetic inactivation of oxysterols controls pNET tumorigenesis by dampening the 24S-HC-neutrophil axis. Finally, we show that in some human pNET samples Cyp46a1 transcripts are overexpressed, which correlate with the HIF-1α target VEGF and with tumor diameter. This study reveals a layer in the angiogenic switch of pNETs and identifies a therapeutic target for pNET patients.oxysterols | HIF-1α | pancreatic neuroendocrine tumors | angiogenic switch | neutrophils R ecent studies have highlighted the diversity of metabolic pathways altered between normal and tumor cells (1, 2). Activation of specific metabolic pathways within tumors is believed to derive from an intricate connection among intrinsic and extrinsic factors, such as oncogenic signaling, stromal-derived molecules, and hypoxia (3). Tumor hypoxia and hypoxia inducible factor-1a (HIF-1α) activation have been linked to increased glucose metabolism and cancer progression in a number of tumor types (4). Whether HIF-1α signaling regulates other metabolic products in tumor cells or during tumorigenesis remains only partially understood.The differential regulation of tumor metabolism and the relative abundance of some tumor-derived metabolites have also been shown to condition the tumor microenvironment, with particular emphasis on immune cell components (5). For example, metabolic products like pyruvic acid and lactic acid induce hypoxiaindependent stabilization of HIF-1α in tumor-associated macrophages (6). These products, especially lactic acid, are products of the so-called Warburg effect (aerobic glycolysis) (7) and mainly require the enzymatic activity of the pyruvate kinase M2 (PKM2), an isoform expressed by tumor cells and associated with the production of high amounts of pyruvate and lactate (8). More recently cholesterol metabolism, oxysterols, and liver X receptors (LXRs) have been shown to be important players in tumor metabolism (9, 10), due to their dual involvement in tumor and immune cell biology (11-13). This dual involvement makes the LXR/oxysterol axis an attractive ta...

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Section: Discussionmentioning

confidence: 99%

24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development

Soncini

Corna

Moresco

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The analysis of in vivo phenotypes is further complicated by the functions of IRF-1 and CH25H in the innate and adaptive immune response (26,39,59,60) and IRF-1 involvement in the DNA damage response, which is known to regulate chronic MHV68 infection (61,62). Dissection of the antiviral mechanism by which IRF-1 suppresses gammaherpesvirus replication and chronic infection is likely to benefit understanding of IRF-1 antiviral functions in the context of other virus families.…”

Section: Discussionmentioning

confidence: 99%

Interferon Regulatory Factor 1 Restricts Gammaherpesvirus Replication in Primary Immune Cells

Mboko

Mounce

Emmer

et al. 2014

J Virol

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Gammaherpesviruses are ubiquitous pathogens that establish a lifelong infection and are associated with cancer. In spite of the high seroprevalence of infection, the risk factors that predispose the host toward gammaherpesvirus-induced malignancies are still poorly understood. Interferon (IFN) regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. On the basis of its biology, IRF-1 represents a plausible host factor to attenuate gammaherpesvirus infection and tumorigenesis. In this study, we show that IRF-1 restricts gammaherpesvirus replication in primary macrophages, a physiologically relevant immune cell type. In spite of the known role of IRF-1 in stimulating type I IFN expression, induction of a global type I IFN response was similar in IRF-1-deficient and -proficient macrophages during gammaherpesvirus infection. However, IRF-1 was required for optimal expression of cholesterol-25-hydroxylase, a host enzyme that restricted gammaherpesvirus replication in primary macrophages and contributed to the antiviral effects of IRF-1. In summary, the current study provides an insight into the mechanism by which IRF-1 attenuates gammaherpesvirus replication in primary immune cells, a mechanism that is likely to contribute to the antiviral effects of IRF-1 in other virus systems. IMPORTANCEInterferon regulatory factor 1 (IRF-1) is a transcription factor that regulates innate and adaptive immune responses and functions as a tumor suppressor. IRF-1 restricts the replication of diverse viruses; however, the mechanisms responsible for the antiviral effects of IRF-1 are still poorly understood. Gammaherpesviruses are ubiquitous pathogens that are associated with the induction of several malignancies. Here we show that IRF-1 expression attenuates gammaherpesvirus replication in primary macrophages, in part by increasing expression of cholesterol-25-hydroxylase (CH25H). CH25H and its product, 25-hydroxycholesterol, restrict replication of diverse virus families. Thus, our findings offer an insight into the mechanism by which IRF-1 attenuates the replication of gammaherpesviruses, a mechanism that is likely to be applicable to other virus systems.

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“…EBI2 is a chemoattractant receptor of the GPCR family with no known roles other than controlling cell migration and/or positioning. Specifically, EBI2 promotes the positioning of dendritic cells and activated B lymphocytes to specialized outer and interfollicular niches in secondary lymphoid organs and plays important roles in primary antibody responses (Gatto et al, 2009(Gatto et al, , 2013Pereira et al, 2009bPereira et al, , 2010aYi et al, 2012;Yi and Cyster, 2013). Thus, the phenotypic similarity between EBI2-and CH25H-deficient mice favor a model in which oxysterols sensed by EBI2 expressed in OCPs regulate bone mass homeostasis predominantly by promoting OCP cell movement and positioning, which facilitates cell fusion and enhances the development of large OCs.…”

Section: Ebi2 Signaling Controls Ocp-directed Migration Toward Bone Smentioning

confidence: 99%

Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis

Nevius¹,

Pinho²,

Dhodapkar³

et al. 2015

J Cell Biol

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Bone surfaces attract hematopoietic and nonhematopoietic cells, such as osteoclasts (OCs) and osteoblasts (OBs), and are targeted by bone metastatic cancers. However, the mechanisms guiding cells toward bone surfaces are essentially unknown. Here, we show that the Gi protein-coupled receptor (GPCR) EBI2 is expressed in mouse monocyte/OC precursors (OCPs) and its oxysterol ligand 7,25-dihydroxycholesterol (7,25-OHC) is secreted abundantly by OBs. Using in vitro time-lapse microscopy and intravital two-photon microscopy, we show that EBI2 enhances the development of large OCs by promoting OCP motility, thus facilitating cell-cell interactions and fusion in vitro and in vivo. EBI2 is also necessary and sufficient for guiding OCPs toward bone surfaces. Interestingly, OCPs also secrete 7,25-OHC, which promotes autocrine EBI2 signaling and reduces OCP migration toward bone surfaces in vivo. Defective EBI2 signaling led to increased bone mass in male mice and protected female mice from age-and estrogen deficiency-induced osteoporosis. This study identifies a novel pathway involved in OCP homing to the bone surface that may have significant therapeutic potential.

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

Cited by 187 publications

References 38 publications

24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development

24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development

Interferon Regulatory Factor 1 Restricts Gammaherpesvirus Replication in Primary Immune Cells

Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis

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