The Experts below are selected from a list of 5103 Experts worldwide ranked by ideXlab platform
Ned A. Porter - One of the best experts on this subject based on the ideXlab platform.
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ozone derived Oxysterols impair lung macrophage phagocytosis via adduction of some phagocytosis receptors
Journal of Biological Chemistry, 2020Co-Authors: Parker F Duffney, Ned A. Porter, Hyeyoung H Kim, Ilona JaspersAbstract:Inhalation of the ambient air pollutant ozone causes lung inflammation and can suppress host defense mechanisms, including impairing macrophage phagocytosis. Ozone reacts with cholesterol in the lung to form Oxysterols, like secosterol A and secosterol B (SecoA and SecoB), which can form covalent adducts on cellular proteins. How Oxysterol-protein adduction modifies the function of lung macrophages is unknown. Herein, we used a proteomic screen to identify lung macrophage proteins that form adducts with ozone-derived Oxysterols. Functional ontology analysis of the adductome indicated that protein binding was a major function of adducted proteins. Further analysis of specific proteins forming adducts with SecoA identified the phagocytic receptors CD206 and CD64. Adduction of these receptors with ozone-derived Oxysterols impaired ligand binding and corresponded with reduced macrophage phagocytosis. This work suggests a novel mechanism for the suppression of macrophage phagocytosis following ozone exposure through the generation of Oxysterols and the formation of Oxysterol-protein adducts on phagocytic receptors.
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Antioxidant Supplementation Ameliorates Molecular Deficits in Smith-Lemli-Opitz Syndrome
Biological Psychiatry, 2013Co-Authors: Zeljka Korade, Refayat Ahsen, Sarah E. Hart, Oakleigh M. Folkes, Karoly Mirnics, Fiona E Harrison, Libin Xu, Ned A. PorterAbstract:Background Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by diminished cholesterol and increased 7-dehydrocholesterol (7-DHC) levels. 7-Dehydrocholesterol is highly reactive, giving rise to biologically active Oxysterols. Methods 7-DHC-derived Oxysterols were measured in fibroblasts from SLOS patients and an in vivo SLOS rodent model using high-performance liquid chromatography tandem mass spectrometry. Expression of lipid biosynthesis genes was ascertained by quantitative polymerase chain reaction and Western blot. The effects of an antioxidant mixture of vitamin A, coenzyme Q10, vitamin C, and vitamin E were evaluated for their potential to reduce formation of 7-DHC Oxysterols in fibroblast from SLOS patients. Finally, the effect of maternal feeding of vitamin E enriched diet was ascertained in the brain and liver of newborn SLOS mice. Results In cultured human SLOS fibroblasts, the antioxidant mixture led to decreased levels of the 7-DHC-derived Oxysterol, 3β,5α-dihydroxycholest-7-en-6-one. Furthermore, gene expression changes in SLOS human fibroblasts were normalized with antioxidant treatment. The active ingredient appeared to be vitamin E, as even at low concentrations, it significantly decreased 3β,5α-dihydroxycholest-7-en-6-one levels. In addition, analyzing a mouse SLOS model revealed that feeding a vitamin E enriched diet to pregnant female mice led to a decrease in Oxysterol formation in brain and liver tissues of the newborn Dhcr7 -knockout pups. Conclusions Considering the adverse effects of 7-DHC-derived Oxysterols in neuronal and glial cultures and the positive effects of antioxidants in patient cell cultures and the transgenic mouse model, we believe that preventing formation of 7-DHC Oxysterols is critical for countering the detrimental effects of DHCR7 mutations.
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Lipid biomarkers of oxidative stress in a genetic mouse model of Smith-Lemli-Opitz syndrome
Journal of Inherited Metabolic Disease, 2013Co-Authors: Zeljka Korade, Karoly Mirnics, Libin Xu, Ned A. PorterAbstract:7-Dehydrocholesterol (7-DHC) accumulates in tissues and fluids of patients with Smith-Lemli-Opitz syndrome (SLOS), which is caused by mutations in the gene encoding 3β-hydrOxysterol-Δ^7-reductase (DHCR7). We recently reported that 7-DHC is the most reactive lipid molecule toward free radical oxidation (lipid peroxidation) and 14 Oxysterols have been identified as products of oxidation of 7-DHC in solution. As the high oxidizability of 7-DHC may lead to systemic oxidative stress in SLOS patients, we report here lipid biomarkers of oxidative stress in a Dhcr7 -KO mouse model of SLOS, including Oxysterols, isoprostanes (IsoPs), and neuroprostanes (NeuroPs) that are formed from the oxidation of 7-DHC, arachidonic acid and docosahexaenoic acid, respectively. In addition to a previously described Oxysterol, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), we provide evidence for the chemical structures of three new Oxysterols in the brain and/or liver tissue of Dhcr7 -KO mice, two of which were quantified. We find that levels of IsoPs and NeuroPs are also elevated in brain and/or liver tissues of Dhcr7 -KO mice relative to matching WT mice. While IsoPs and NeuroPs have been established as a reliable measurement of lipid peroxidation and oxidative stress in vivo, we show that in this genetic SLOS mouse model, 7-DHC-derived Oxysterols are present at much higher levels than IsoPs and NeuroPs and thus are better markers of lipid oxidation and related oxidative stress.
Isabelle Delton-vandenbroucke - One of the best experts on this subject based on the ideXlab platform.
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In vitro oxidized HDL and HDL from type 2 diabetes patients have reduced ability to efflux Oxysterols from THP-1 macrophages
Biochimie, 2018Co-Authors: Yinan Chen, Maud Arnal-levron, Françoise Hullin-matsuda, Carole Knibbe, Philippe Moulin, Céline Luquain-costaz, Isabelle Delton-vandenbrouckeAbstract:Oxidized LDL (OxLDL) that are enriched in products of lipid peroxidation including Oxysterols have been shown to induce cellular oxidative stress and cytotoxicity therefore accelerating atheroma plaque formation. Upon oxLDL exposure of THP-1 macrophages, intracellular oxidation of LDL derived-cholesterol as well as endogenous cholesterol was increased. The Oxysterols intracellularly produced were efficiently exported to HDL whereas apolipoprotein A1 was inefficient. These findings prompted us to investigate the consequences of modification of HDL by oxidation and glycation as observed in type 2 diabetes with respect to Oxysterol and cholesterol efflux. We show that efflux of Oxysterols was significantly impaired after in vitro oxidation and glycoxidation of HDL whereas glycation alone had no impact. Cholesterol efflux was only slightly decreased by oxHDL or glycoxidized HDL and not changed with glycated HDL. The defect of HDL towards Oxysterol efflux was also observed with HDL isolated from diabetic subjects as compared to healthy controls. These findings support a deleterious cellular retention of Oxysterols due to dysfunctional HDL in type 2 diabetes.
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THP1 macrophages oxidized cholesterol, generating 7-derivative Oxysterols specifically released by HDL
Steroids, 2015Co-Authors: Yinan Chen, Maud Arnal-levron, Philippe Moulin, Céline Luquain-costaz, Michel Lagarde, Isabelle Delton-vandenbrouckeAbstract:Macrophages are well recognized as key pathophysiologic agents in many chronic inflammatory diseases, especially atherosclerosis. During atherogenesis process, low density lipoproteins (LDL) undergo oxidation (oxLDL) and become highly atherogenic as they induce a strong accumulation of cholesterol in subendothelial macrophages leading to the formation of foam cells, the major cellular component of fatty streaks. OxLDL are enriched in oxidation products of cholesterol called Oxysterols involved in the regulation of cholesterol homeostasis, by their ability to induce cellular oxidative stress and cytotoxicity. Little is known about intracellular Oxysterol production in macrophages. Using both radiochemical and mass analyzes, we showed that THP1 macrophages promote the intracellular oxidation of LDL derived-cholesterol as well as intracellular cholesterol, this later mechanism being enhanced by exposure with native or oxLDL. We demonstrated that in both THP1 and Raw 267.4 cells cholesterol oxidation occurs in the late endosomal compartment. Most Oxysterols were produced by non-enzymatic routes (7-ketocholesterol and 7alpha/beta-hydroxycholesterol) but enzymatically formed 7alpha-, 27-hydroxycholesterol were also quantified. Incubation of THP1 macrophages with nLDL or oxLDL, induced a 2- and 100-fold increase in Oxysterol production, respectively. Both Oxysterols derived from LDL cholesterol and cellular cholesterol were readily exported to HDL whereas apoA1 was inefficient, showing that HDL plays a major role in the removal of excess Oxysterols in THP1 macrophages.
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Bis(monoacylglycero)phosphate reduces Oxysterol formation and apoptosis in macrophages exposed to oxidized LDL.
Biochemical Pharmacology, 2013Co-Authors: Maud Arnal-levron, Yinan Chen, Isabelle Delton-vandenbroucke, Céline Luquain-costazAbstract:Atherosclerosis is a major cardiovascular complication of diseases associated with increased oxidative stress that favors oxidation of circulating low density lipoproteins (LDLs). Oxidized LDL (oxLDL) is considered as highly atherogenic as it induces a strong accumulation of cholesterol in subendothelial macrophages leading to the formation of foam cells and emergence of atherosclerotic plaque. OxLDL is enriched in oxidation products of cholesterol called Oxysterols, some of which have been involved in the ability of oxLDL to induce cellular oxidative stress and cytotoxicity, mainly by apoptosis. Little is known about the possible contribution of cell-generated Oxysterols toward LDL-associated Oxysterols in cellular accumulation of Oxysterols and related apoptosis. Using both radiochemical and mass analyzes, we showed that oxLDL greatly enhanced Oxysterol production by RAW macrophages in comparison with unloaded cells or cells loaded with native LDL. Most Oxysterols were produced by non-enzymatic routes (7-ketocholesterol and 7α/β-hydroyxycholesterol) but enzymatically formed 7α-, 25- and 27-hydroxycholesterol were also quantified. Bis(monoacylglycero)phosphate (BMP) is a unique phospholipid preferentially found in late endosomes. We and others have highlighted the role of BMP in the regulation of intracellular cholesterol metabolism/traffic in macrophages. We here report that cellular BMP accumulation was associated with a significantly lower production of Oxysterols upon oxLDL exposure. Of note, potent pro-apoptotic 7-ketocholesterol was the most markedly decreased. OxLDL-induced cell cytotoxicity and apoptosis were consistently attenuated in BMP-enriched cells. Taken together, our data suggest that BMP exerts a protective action against the pro-apoptotic effect of oxLDL via a reduced production of intracellular pro-apoptotic Oxysterols.
Laura Raccosta - One of the best experts on this subject based on the ideXlab platform.
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24 hydroxycholesterol participates in pancreatic neuroendocrine tumor development
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Matias Soncini, Gianfranca Corna, Nadia Coltella, Umberto Restuccia, Daniela Maggioni, Laura Raccosta, Francesca Invernizzi, Roberto Crocchiolo, Marta Moresco, Claudio DoglioniAbstract:Abstract 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 tumor-derived 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.
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Cholesterol metabolites and tumor microenvironment: the road towards clinical translation
Cancer Immunology Immunotherapy, 2016Co-Authors: Laura Raccosta, Gianfranca Corna, Daniela Maggioni, Marta Moresco, Raffaella Fontana, Vincenzo RussoAbstract:Targeting the tumor microenvironment focusing on immune cells has recently become a standard of care for some tumors. Indeed, antibodies blocking immune checkpoints (e.g., anti-CTLA-4 and anti-PD1 mAbs) have been approved by regulatory agencies for the treatment of some solid tumors based upon successes in many clinical trials. Although tumor metabolism has always attracted the attention of tumor biologists, only recently have oncologists renewed their interest in this field of tumor biology research. This has highlighted the possibility to pharmacologically target rate-limiting enzymes along key metabolic pathways of tumor cells, such as lipogenesis and aerobic glycolysis. Altered tumor metabolism has also been shown to influence the functionality of the tumor microenvironment as a whole, particularly the immune cell component of thereof. Cholesterol, Oxysterols and Liver X receptors (LXRs) have been investigated in different tumor models. Recent in vitro and in vivo results point to their involvement in tumor and immune cell biology, thus making the LXR/Oxysterol axis a possible target for novel antitumor strategies. Indeed, the possibility to target both tumor cell metabolism (i.e., cholesterol metabolism) and tumor-infiltrating immune cell dysfunctions induced by Oxysterols might result in a synergistic antitumor effect generating long-lasting memory responses. This review will focus on the role of cholesterol metabolism with particular emphasis on the role of the LXR/Oxysterol axis in the tumor microenvironment, discussing mechanisms of action, pros and cons, and strategies to develop antitumor therapies based on the modulation of this axis.
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the Oxysterol cxcr2 axis plays a key role in the recruitment of tumor promoting neutrophils
Journal of Experimental Medicine, 2013Co-Authors: Laura Raccosta, Daniela Maggioni, Raffaella Fontana, Claudia Lanterna, Eduardo J Villablanca, Aida Paniccia, Andrea Musumeci, Elena Chiricozzi, Maria Letizia Trincavelli, Simona DanieleAbstract: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.
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abstract lb 346 the Oxysterol cxcr2 axis plays a key role in the recruitment of tumor promoting neutrophils
Cancer Research, 2013Co-Authors: Vincenzo Russo, Daniela Maggioni, Laura Raccosta, Claudio Doglioni, Raffaella Fontana, Claudia Lanterna, Aida Paniccia, Andrea Musumeci, Andrea Leiva, Eduardo J VillablancaAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Tumor formation depends on molecular alterations responsible for neoplastic transformation of normal cells, as well as on the ability of tumor cells to co-opt inflammatory/immune cells to create a tumor growth-permissive microenvironment. Targeted therapies inhibiting molecular alterations in tumor cells have improved antitumor responses. However, overall survival has been enhanced only slightly. Tumor-infiltrating immune cells can be conditioned by molecules released within the microenvironment to thwart antitumor immune responses. Among immune cells, neutrophils are recognized as playing an important pro-tumorigenic role, by favoring neoangiogenesis and/or by suppressing antitumor immune responses. We have recently shown that tumor-derived Liver X Receptor (LXR) ligands/Oxysterols, known to be involved in cholesterol homeostasis and in modulating physiologic immune responses, favor tumor growth by inhibiting dendritic cell migration towards lymphoid organs. Here, we identify an unanticipated function of tumor-derived LXR ligands/Oxysterols, which contribute to the recruitment of neutrophils within tumor microenvironment in an LXR-independent, CXCR2-dependent manner, ultimately favoring tumor growth. In particular, we show a continuous recruitment of neutrophils in Oxysterol-releasing tumors, as evaluated by parabiosis experiments. We demonstrate by mass spectrometry and high-performance liquid chromatography analyses that the lymphoma RMA, the Lewis Lung Carcinoma (LLC) and the mesothelioma AB1 produce some Oxysterols (22R-HC, 27-HC and 24S-HC), which are able to induce CD11b+Ly6G+ neutrophil migration in vitro and in vivo. Neutrophil migration is independent of LXR signaling both in vitro and in vivo, as demonstrated by using Lxrαβ-/- mice, while it depends on the Oxysterol-CXCR2 interaction, as evaluated in vitro by migration experiments with Cxcr2-/- neutrophils, GTPγS binding assays, measurements of cAMP levels, and, in vivo by tumor challenge experiments in Cxcr2-/- bone marrow chimera mice. Tumor-recruited neutrophils are then able to favor tumor growth by promoting neoangiogenesis or immunosuppression of antitumor responses. Furthermore, we demonstrate that RMA, LLC and AB1 tumors engineered to express the Oxysterol-inactivating enzyme sulfotransferase 2B1b (SULT2B1b), show a reduced number of tumor-infiltrating neutrophils as well as of CD31+CD45- endothelial cells, as compared to mock-expressing tumors. This reduction parallels tumor growth delay and prolonged survival of SULT2B1b-tumor-bearing mice. Antitumor responses are also obtained with genetic or pharmacologic inactivation of CXCR2, the latter mediated by the CXCR2 antagonist SB225002. These results, along with the observation that some human tumors release Oxysterols, identify an unanticipated pro-tumor function of the Oxysterol-CXCR2 axis and a possible new target for cancer therapy. Citation Format: Vincenzo Russo, Laura Raccosta, Raffaella Fontana, Daniela Maggioni, Claudia Lanterna, Aida Paniccia, Andrea Musumeci, Claudio Doglioni, Andrea Leiva, Eduardo J. Villablanca, Rodrigo Mora, Elena Chiricozzi, Maria Grazia Ciampa, Laura Mauri, Alessandro Prinetti, Sandro Sonino, Maria Letizia Trincavelli, Simona Daniele, Claudia Martini, Knut Steffensen, Jan-Ake Gustafsson, Safiye Gozalvo Feo, Claudio Bordignon, Catia Traversari, Silvano Sozzani. The Oxysterol-CXCR2 axis plays a key role in the recruitment of tumor promoting neutrophils. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-346. doi:10.1158/1538-7445.AM2013-LB-346
Daniela Maggioni - One of the best experts on this subject based on the ideXlab platform.
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24 hydroxycholesterol participates in pancreatic neuroendocrine tumor development
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Matias Soncini, Gianfranca Corna, Nadia Coltella, Umberto Restuccia, Daniela Maggioni, Laura Raccosta, Francesca Invernizzi, Roberto Crocchiolo, Marta Moresco, Claudio DoglioniAbstract:Abstract 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 tumor-derived 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.
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Cholesterol metabolites and tumor microenvironment: the road towards clinical translation
Cancer Immunology Immunotherapy, 2016Co-Authors: Laura Raccosta, Gianfranca Corna, Daniela Maggioni, Marta Moresco, Raffaella Fontana, Vincenzo RussoAbstract:Targeting the tumor microenvironment focusing on immune cells has recently become a standard of care for some tumors. Indeed, antibodies blocking immune checkpoints (e.g., anti-CTLA-4 and anti-PD1 mAbs) have been approved by regulatory agencies for the treatment of some solid tumors based upon successes in many clinical trials. Although tumor metabolism has always attracted the attention of tumor biologists, only recently have oncologists renewed their interest in this field of tumor biology research. This has highlighted the possibility to pharmacologically target rate-limiting enzymes along key metabolic pathways of tumor cells, such as lipogenesis and aerobic glycolysis. Altered tumor metabolism has also been shown to influence the functionality of the tumor microenvironment as a whole, particularly the immune cell component of thereof. Cholesterol, Oxysterols and Liver X receptors (LXRs) have been investigated in different tumor models. Recent in vitro and in vivo results point to their involvement in tumor and immune cell biology, thus making the LXR/Oxysterol axis a possible target for novel antitumor strategies. Indeed, the possibility to target both tumor cell metabolism (i.e., cholesterol metabolism) and tumor-infiltrating immune cell dysfunctions induced by Oxysterols might result in a synergistic antitumor effect generating long-lasting memory responses. This review will focus on the role of cholesterol metabolism with particular emphasis on the role of the LXR/Oxysterol axis in the tumor microenvironment, discussing mechanisms of action, pros and cons, and strategies to develop antitumor therapies based on the modulation of this axis.
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the Oxysterol cxcr2 axis plays a key role in the recruitment of tumor promoting neutrophils
Journal of Experimental Medicine, 2013Co-Authors: Laura Raccosta, Daniela Maggioni, Raffaella Fontana, Claudia Lanterna, Eduardo J Villablanca, Aida Paniccia, Andrea Musumeci, Elena Chiricozzi, Maria Letizia Trincavelli, Simona DanieleAbstract: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.
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abstract lb 346 the Oxysterol cxcr2 axis plays a key role in the recruitment of tumor promoting neutrophils
Cancer Research, 2013Co-Authors: Vincenzo Russo, Daniela Maggioni, Laura Raccosta, Claudio Doglioni, Raffaella Fontana, Claudia Lanterna, Aida Paniccia, Andrea Musumeci, Andrea Leiva, Eduardo J VillablancaAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Tumor formation depends on molecular alterations responsible for neoplastic transformation of normal cells, as well as on the ability of tumor cells to co-opt inflammatory/immune cells to create a tumor growth-permissive microenvironment. Targeted therapies inhibiting molecular alterations in tumor cells have improved antitumor responses. However, overall survival has been enhanced only slightly. Tumor-infiltrating immune cells can be conditioned by molecules released within the microenvironment to thwart antitumor immune responses. Among immune cells, neutrophils are recognized as playing an important pro-tumorigenic role, by favoring neoangiogenesis and/or by suppressing antitumor immune responses. We have recently shown that tumor-derived Liver X Receptor (LXR) ligands/Oxysterols, known to be involved in cholesterol homeostasis and in modulating physiologic immune responses, favor tumor growth by inhibiting dendritic cell migration towards lymphoid organs. Here, we identify an unanticipated function of tumor-derived LXR ligands/Oxysterols, which contribute to the recruitment of neutrophils within tumor microenvironment in an LXR-independent, CXCR2-dependent manner, ultimately favoring tumor growth. In particular, we show a continuous recruitment of neutrophils in Oxysterol-releasing tumors, as evaluated by parabiosis experiments. We demonstrate by mass spectrometry and high-performance liquid chromatography analyses that the lymphoma RMA, the Lewis Lung Carcinoma (LLC) and the mesothelioma AB1 produce some Oxysterols (22R-HC, 27-HC and 24S-HC), which are able to induce CD11b+Ly6G+ neutrophil migration in vitro and in vivo. Neutrophil migration is independent of LXR signaling both in vitro and in vivo, as demonstrated by using Lxrαβ-/- mice, while it depends on the Oxysterol-CXCR2 interaction, as evaluated in vitro by migration experiments with Cxcr2-/- neutrophils, GTPγS binding assays, measurements of cAMP levels, and, in vivo by tumor challenge experiments in Cxcr2-/- bone marrow chimera mice. Tumor-recruited neutrophils are then able to favor tumor growth by promoting neoangiogenesis or immunosuppression of antitumor responses. Furthermore, we demonstrate that RMA, LLC and AB1 tumors engineered to express the Oxysterol-inactivating enzyme sulfotransferase 2B1b (SULT2B1b), show a reduced number of tumor-infiltrating neutrophils as well as of CD31+CD45- endothelial cells, as compared to mock-expressing tumors. This reduction parallels tumor growth delay and prolonged survival of SULT2B1b-tumor-bearing mice. Antitumor responses are also obtained with genetic or pharmacologic inactivation of CXCR2, the latter mediated by the CXCR2 antagonist SB225002. These results, along with the observation that some human tumors release Oxysterols, identify an unanticipated pro-tumor function of the Oxysterol-CXCR2 axis and a possible new target for cancer therapy. Citation Format: Vincenzo Russo, Laura Raccosta, Raffaella Fontana, Daniela Maggioni, Claudia Lanterna, Aida Paniccia, Andrea Musumeci, Claudio Doglioni, Andrea Leiva, Eduardo J. Villablanca, Rodrigo Mora, Elena Chiricozzi, Maria Grazia Ciampa, Laura Mauri, Alessandro Prinetti, Sandro Sonino, Maria Letizia Trincavelli, Simona Daniele, Claudia Martini, Knut Steffensen, Jan-Ake Gustafsson, Safiye Gozalvo Feo, Claudio Bordignon, Catia Traversari, Silvano Sozzani. The Oxysterol-CXCR2 axis plays a key role in the recruitment of tumor promoting neutrophils. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-346. doi:10.1158/1538-7445.AM2013-LB-346
Yinan Chen - One of the best experts on this subject based on the ideXlab platform.
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Bis(monoacylglycero)phosphate regulates Oxysterol binding protein-related protein 11 dependent sterol trafficking
Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids, 2019Co-Authors: Maud Arnal-levron, Yinan Chen, Françoise Hullin-matsuda, Peter Greimel, Federica Calevro, Karen Gaget, Fabien Riols, Aurélie Batut, Justine Bertrand-michel, Vesa OlkkonenAbstract:Bis(Monoacylglycero) Phosphate (BMP) is a unique phospholipid localized in late endosomes, a critical cellular compartment in low density lipoprotein (LDL)-cholesterol metabolism. In previous work, we demonstrated the important role of BMP in the regulation of macrophage cholesterol homeostasis. BMP exerts a protective role against the pro-apoptotic effect of oxidized LDL (oxLDL) by reducing the production of deleterious Oxysterols. As the intracellular sterol traffic in macrophages is in part regulated by Oxysterol binding protein (OSBP) and OSBP-related proteins (ORPs), we investigated the role of ORP11, localized at the Golgi-late endosomes interface, in the BMP-mediated protection from oxLDL/Oxysterol cytotoxicity. Stably silencing of ORP11 in mouse RAW264.7 macrophages via a shRNA lentiviruses system had no effect on BMP production. However, ORP11 knockdown abrogated the protective action of BMP against oxLDL induced apoptosis. In oxLDL treated control cells, BMP enrichment was associated with reduced generation of 7-Oxysterols, while these Oxysterol species were abundant in the ORP11 knock-down cells. Of note, BMP enrichment in ORP11 knock-down cells was associated with a drastic increase in free cholesterol and linked to a decrease of cholesterol efflux. The expression of ATP-binding cassette-transporter G1 (ABCG1) was also reduced in the ORP11 knock-down cells. These observations demonstrate a cooperative function of OPR11 and BMP, in intracellular cholesterol trafficking in cultured mac-rophages. We suggest that BMP favors the egress of cholesterol from late endosomes via an ORP11-dependent mechanism, resulting in a reduced production of cytotoxic 7-Oxysterols.
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In vitro oxidized HDL and HDL from type 2 diabetes patients have reduced ability to efflux Oxysterols from THP-1 macrophages
Biochimie, 2018Co-Authors: Yinan Chen, Maud Arnal-levron, Françoise Hullin-matsuda, Carole Knibbe, Philippe Moulin, Céline Luquain-costaz, Isabelle Delton-vandenbrouckeAbstract:Oxidized LDL (OxLDL) that are enriched in products of lipid peroxidation including Oxysterols have been shown to induce cellular oxidative stress and cytotoxicity therefore accelerating atheroma plaque formation. Upon oxLDL exposure of THP-1 macrophages, intracellular oxidation of LDL derived-cholesterol as well as endogenous cholesterol was increased. The Oxysterols intracellularly produced were efficiently exported to HDL whereas apolipoprotein A1 was inefficient. These findings prompted us to investigate the consequences of modification of HDL by oxidation and glycation as observed in type 2 diabetes with respect to Oxysterol and cholesterol efflux. We show that efflux of Oxysterols was significantly impaired after in vitro oxidation and glycoxidation of HDL whereas glycation alone had no impact. Cholesterol efflux was only slightly decreased by oxHDL or glycoxidized HDL and not changed with glycated HDL. The defect of HDL towards Oxysterol efflux was also observed with HDL isolated from diabetic subjects as compared to healthy controls. These findings support a deleterious cellular retention of Oxysterols due to dysfunctional HDL in type 2 diabetes.
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THP1 macrophages oxidized cholesterol, generating 7-derivative Oxysterols specifically released by HDL
Steroids, 2015Co-Authors: Yinan Chen, Maud Arnal-levron, Philippe Moulin, Céline Luquain-costaz, Michel Lagarde, Isabelle Delton-vandenbrouckeAbstract:Macrophages are well recognized as key pathophysiologic agents in many chronic inflammatory diseases, especially atherosclerosis. During atherogenesis process, low density lipoproteins (LDL) undergo oxidation (oxLDL) and become highly atherogenic as they induce a strong accumulation of cholesterol in subendothelial macrophages leading to the formation of foam cells, the major cellular component of fatty streaks. OxLDL are enriched in oxidation products of cholesterol called Oxysterols involved in the regulation of cholesterol homeostasis, by their ability to induce cellular oxidative stress and cytotoxicity. Little is known about intracellular Oxysterol production in macrophages. Using both radiochemical and mass analyzes, we showed that THP1 macrophages promote the intracellular oxidation of LDL derived-cholesterol as well as intracellular cholesterol, this later mechanism being enhanced by exposure with native or oxLDL. We demonstrated that in both THP1 and Raw 267.4 cells cholesterol oxidation occurs in the late endosomal compartment. Most Oxysterols were produced by non-enzymatic routes (7-ketocholesterol and 7alpha/beta-hydroxycholesterol) but enzymatically formed 7alpha-, 27-hydroxycholesterol were also quantified. Incubation of THP1 macrophages with nLDL or oxLDL, induced a 2- and 100-fold increase in Oxysterol production, respectively. Both Oxysterols derived from LDL cholesterol and cellular cholesterol were readily exported to HDL whereas apoA1 was inefficient, showing that HDL plays a major role in the removal of excess Oxysterols in THP1 macrophages.
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Bis(monoacylglycero)phosphate reduces Oxysterol formation and apoptosis in macrophages exposed to oxidized LDL.
Biochemical Pharmacology, 2013Co-Authors: Maud Arnal-levron, Yinan Chen, Isabelle Delton-vandenbroucke, Céline Luquain-costazAbstract:Atherosclerosis is a major cardiovascular complication of diseases associated with increased oxidative stress that favors oxidation of circulating low density lipoproteins (LDLs). Oxidized LDL (oxLDL) is considered as highly atherogenic as it induces a strong accumulation of cholesterol in subendothelial macrophages leading to the formation of foam cells and emergence of atherosclerotic plaque. OxLDL is enriched in oxidation products of cholesterol called Oxysterols, some of which have been involved in the ability of oxLDL to induce cellular oxidative stress and cytotoxicity, mainly by apoptosis. Little is known about the possible contribution of cell-generated Oxysterols toward LDL-associated Oxysterols in cellular accumulation of Oxysterols and related apoptosis. Using both radiochemical and mass analyzes, we showed that oxLDL greatly enhanced Oxysterol production by RAW macrophages in comparison with unloaded cells or cells loaded with native LDL. Most Oxysterols were produced by non-enzymatic routes (7-ketocholesterol and 7α/β-hydroyxycholesterol) but enzymatically formed 7α-, 25- and 27-hydroxycholesterol were also quantified. Bis(monoacylglycero)phosphate (BMP) is a unique phospholipid preferentially found in late endosomes. We and others have highlighted the role of BMP in the regulation of intracellular cholesterol metabolism/traffic in macrophages. We here report that cellular BMP accumulation was associated with a significantly lower production of Oxysterols upon oxLDL exposure. Of note, potent pro-apoptotic 7-ketocholesterol was the most markedly decreased. OxLDL-induced cell cytotoxicity and apoptosis were consistently attenuated in BMP-enriched cells. Taken together, our data suggest that BMP exerts a protective action against the pro-apoptotic effect of oxLDL via a reduced production of intracellular pro-apoptotic Oxysterols.
