Regulated Accumulation of Desmosterol Integrates Macrophage Lipid Metabolism and Inflammatory Responses

Spann, Nathanael J.; Garmire, Lana X.; McDonald, Jeffrey G.; Myers, David S.; Milne, Stephen; Shibata, Norihito; Reichart, Donna; Fox, Jesse N.; Shaked, Iftach; Heudobler, Daniel; Raetz, Christian R. H.; Wang, Elaine W.; Kelly, Samuel; Sullards, M. Cameron; Murphy, Robert C.; Merrill, Alfred H.; Brown, Heather A.; Dennis, Edward A.; Li, Andrew C.; Ley, Klaus; Tsimikas, Sotirios; Fahy, Eoin; Subramaniam, Shankar; Quehenberger, Oswald; Russell, David W.; Glass, Christopher K.

doi:10.1016/j.cell.2012.06.054

Cited by 518 publications

(549 citation statements)

References 45 publications

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“…The important role of adenosine in neonatal macrophages and differences in their lipid and glucose metabolism was supported by an increased expression of factors such as adenosine deaminase, 24-dehydrocholesterol reductase, and glucose-6-phosphate dehydrogenase as shown in network No.3 (37). All these factors are also known to modulate the inflammatory response [45].…”

Section: Discussionmentioning

confidence: 99%

Distinct phenotypic features of neonatal murine macrophages

et al. 2014

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Neonates rely on their innate immune system. Resident tissue macrophages are considered to be initiators and regulators of the innate immune response and thus, appear to be especially important to neonates. We hypothesized that the phenotype and function of neonatal tissue macrophages differ from their adult counterparts. Peritoneal macrophages from neonatal (<24 h) and adult (6 weeks old) C57BL/6J mice were isolated and analyzed by high-content chipcytometry. After stimulation for 6 h with LPS (0, 1, 10, 100 ng/mL), macrophage transcriptome was analyzed by microarray and cytokine release was measured using multiparametric bead assays. Antigen presenting capacity was compared by T-cell stimulation assays. We observed that neonatal murine peritoneal macrophages are characterized by selective lack of expression of F4/80, MHC class II, and costimulatory molecules (CD80, CD86). Furthermore, we found differences in the transcriptome between neonatal and adult macrophages, unstimulated and after LPS stimulation. Although neonatal macrophages showed a significantly increased secretion of proinflammatory cytokines upon LPS stimulation, their potential to induce T-cell proliferation was significantly reduced. In conclusion, we observed a distinct phenotype of the neonatal macrophage population. The specific functions of this macrophage population could help to understand the excessive inflammatory reactions observed in the very young.Keywords: Immune responses r Macrophages r Neonate immunity r Toll-like receptors (TLRs) Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNeonates and in particular preterm infants are extremely vulnerable to states of inflammation [1]. They have an increased susceptibility to microbial infections with an enhanced morbidity and Correspondence: Mr. Thomas Winterberg e-mail: Winterberg.thomas@mh-hannover.de mortality [2]. Sepsis, pneumonia, and gastrointestinal disorders such as necrotizing enterocolitis are a common threat to patients in neonatal intensive care. The first days of life represent a period of transition of the immune system: The protection of the fetus by the maternal immune system and the sterile environment are lost and the newborn has to cope with the outside world and its multiple foreign antigens. Although maternal antibodies help the neonate in the first weeks, it has to develop its own adaptive immune capacities during infancy [2]. In the neonatal period, monocytes and [6][7][8][9]. Until now, neonatal monocytes and macrophages have been described as immature or dormant myeloid cells. However, these studies are based on peripheral blood monocytes or CBMs, which further differentiate into macrophages ex vivo. Little is known about tissue macrophages in neonates, due to technical difficulties of their isolation and evaluation, but a recent study demonstrated their unique function during heart tissue regeneration [10].It has been shown that the heterogeneous murine macrophage populations are orig...

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Section: Discussionmentioning

confidence: 99%

Distinct phenotypic features of neonatal murine macrophages

et al. 2014

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“…Therefore, they occupy a distinct microenvironment relative to lipid-laden foam cell macrophages. In the plaque's necrotic core, oxidized LDL (oxLDL) is bound to scavenger receptors including CD36, SR-A/B, and LOX-1 on macrophages (163 (162). However, when HO-1-deficient macrophages are treated with oxLDL, generation of ROS is amplified and secretion of pro-inflammatory IL-6, MCP-1, and the IL-8 homologue, KC is increased (128).…”

Section: Ho-1 and Atheroprotective Macrophagesmentioning

confidence: 99%

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

Hull

Agarwal

George

2014

Antioxidants & Redox Signaling

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Significance: Heme oxygenase-1 (HO-1) is a potential therapeutic target in many diseases, especially those mediated by oxidative stress and inflammation. HO-1 expression appears to regulate the homeostatic activity and distribution of mononuclear phagocytes ( MP) in lymphoid tissue under physiological conditions. It also regulates the ability of MP to modulate the inflammatory response to tissue injury. Recent Advances: The induction of HO-1 within MP-particularly macrophages and dendritic cells-modulates the effector functions that they acquire after activation. These effector functions include cytokine production, surface receptor expression, maturation state, and polarization toward a pro-or anti-inflammatory phenotype. The importance of HO-1 in MP is emphasized by their expression of specific receptors that primarily function to ingest heme-containing substrate and deliver it to HO-1. Critical Issues: MP are the first immunological responders to tissue damage. They critically affect the outcome of injury to many organ systems, yet few therapies are currently available to specifically target MP during disease pathogenesis. Elucidation of the role of HO-1 expression in MP may help to direct broadly applicable therapies to clinical use that are based on the immunomodulatory capabilities of HO-1. Future Directions: Unraveling the complexities of HO-1 expression specifically within MP will more completely define how HO-1 provides cytoprotection in vivo. The use of models in which HO-1 expression is specifically modulated in bone marrow-derived cells will allow for a more complete characterization of its immunoregulatory properties.

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“…The main LDL modifications related to atherosclerosis development involve lipid peroxidation 5. Transcriptional response of macrophages to exposure to oxidized (ox) LDL has been tested in cultured macrophages of different sources, with diverse results that, depending on the study, suggested predominantly proinflammatory or anti‐inflammatory effects 6, 7, 8, 9. In some cases, the outcome was significantly affected by changes in experimental variables, such as the cell type, form of LDL modification and presentation to cells, or time of exposure to the lipoproteins.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate‐Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation

Goo

Son

Yechoor

et al. 2016

JAHA

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BackgroundFoam cells are central to two major pathogenic processes in atherogenesis: cholesterol buildup in arteries and inflammation. The main underlying cause of cholesterol deposition in arteries is hypercholesterolemia. This study aimed to assess, in vivo, whether elevated plasma cholesterol also alters the inflammatory balance of foam cells.Methods and ResultsApolipoprotein E–deficient mice were fed regular mouse chow through the study or were switched to a Western‐type diet (WD) 2 or 14 weeks before death. Consecutive sections of the aortic sinus were used for lesion quantification or to isolate RNA from foam cells by laser‐capture microdissection (LCM) for microarray and quantitative polymerase chain reaction analyses. WD feeding for 2 or 14 weeks significantly increased plasma cholesterol, but the size of atherosclerotic lesions increased only in the 14‐week WD group. Expression of more genes was affected in foam cells of mice under prolonged hypercholesterolemia than in mice fed WD for 2 weeks. However, most transcripts coding for inflammatory mediators remained unchanged in both WD groups. Among the main players in inflammatory or immune responses, chemokine (C‐X‐C motif) ligand 13 was induced in foam cells of mice under WD for 2 weeks. The interferon‐inducible GTPases, guanylate‐binding proteins (GBP)3 and GBP6, were induced in the 14‐week WD group, and other GBP family members were moderately increased.ConclusionsOur results indicate that acceleration of atherosclerosis by hypercholesterolemia is not linked to global changes in the inflammatory balance of foam cells. However, induction of GBPs uncovers a novel family of immune modulators with a potential role in atherogenesis.

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Regulated Accumulation of Desmosterol Integrates Macrophage Lipid Metabolism and Inflammatory Responses

Cited by 518 publications

References 45 publications

Distinct phenotypic features of neonatal murine macrophages

Distinct phenotypic features of neonatal murine macrophages

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate‐Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation

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