SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism

Oishi, Yumiko; Spann, Nathanael J.; Link, Verena M.; Muse, Evan D.; Strid, Tobias; Edillor, Chantle; Kolar, Matthew J.; Matsuzaka, Takashi; Hayakawa, Sumio; Tao, Jenhan; Kaikkonen, Minna U.; Carlin, Aaron F.; Lam, Michael T.; Manabe, Ichiro; Shimano, Hitoshi; Saghatelian, Alan; Glass, Christopher K.

doi:10.1016/j.cmet.2016.11.009

Cited by 264 publications

(252 citation statements)

References 46 publications

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“…Furthermore, Li et al [41] suggest up-regulation of LXR-regulated genes encoding enzymes involved in the synthesis of long chain PUFAs with known antiinflammatory activity including palmitoleic acid, eicospentaenoic acid (EPA), and docosahexaenoic acid (DHA) is essential for the anti-inflammatory phenotype observed in Ncor1 knockout mice. The observation that treatment of macrophages with LPS in vitro transiently inhibits fatty acid synthesis [5] further supports the hypothesis that fatty acids may play important roles in limiting inflammation. The re-establishment of fatty acid synthesis observed at later stages after LPS administration has been proposed to play a role in the subsequent resolution of the inflammatory response [5].…”

Section: Linking Lipid Metabolism and Inflammationsupporting

confidence: 63%

“…Initial studies using electrophoretic shift mobility assays and promoter analyses identified direct repeats of the classic nuclear receptor‐binding motif AGGTCA separated by four nucleotides (DR4) or inverted repeats of the same sequence separated by 1 nucleotide (IR1) as high‐affinity binding sites for LXR‐RXR heterodimers . These sequence preferences have largely been confirmed by genome‐wide chromatin immunoprecipitation sequence experiments .…”

Section: Dna Binding and Transcriptional Controlmentioning

confidence: 96%

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Liver X receptors link lipid metabolism and inflammation

2017

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The response of immune cells to pathogens is often associated with changes in the flux through basic metabolic pathways. Indeed, in many cases changes in metabolism appear to be necessary for a robust immune response. The Liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that regulate gene networks controlling cholesterol and lipid metabolism. In immune cells, particularly in macrophages, LXRs also inhibit pro-inflammatory gene expression. This Review will highlight recent studies that connect LXR-dependent control of lipid metabolism to regulation of the immune response.

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Section: Linking Lipid Metabolism and Inflammationsupporting

confidence: 63%

Section: Dna Binding and Transcriptional Controlmentioning

confidence: 96%

Liver X receptors link lipid metabolism and inflammation

2017

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“…Weak interactions were also detected between F12-like and NF-KB p65 and RNA Pol II in thioglycolate-elicited MFs [191]. …”

Section: Resultsmentioning

confidence: 99%

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Cellier

2017

Biology

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NRAMP1 (SLC11A1) is a professional phagocyte membrane importer of divalent metals that contributes to iron recycling at homeostasis and to nutritional immunity against infection. Analyses of data generated by several consortia and additional studies were integrated to hypothesize mechanisms restricting NRAMP1 expression to mature phagocytes. Results from various epigenetic and transcriptomic approaches were collected for mesodermal and hematopoietic cell types and compiled for combined analysis with results of genetic studies associating single nucleotide polymorphisms (SNPs) with variations in NRAMP1 expression (eQTLs). Analyses establish that NRAMP1 is part of an autonomous topologically associated domain delimited by ubiquitous CCCTC-binding factor (CTCF) sites. NRAMP1 locus contains five regulatory regions: a predicted super-enhancer (S-E) key to phagocyte-specific expression; the proximal promoter; two intronic areas, including 3′ inhibitory elements that restrict expression during development; and a block of upstream sites possibly extending the S-E domain. Also the downstream region adjacent to the 3′ CTCF locus boundary may regulate expression during hematopoiesis. Mobilization of the locus 14 predicted transcriptional regulatory elements occurs in three steps, beginning with hematopoiesis; at the onset of myelopoiesis and through myelo-monocytic differentiation. Basal expression level in mature phagocytes is further influenced by genetic variation, tissue environment, and in response to infections that induce various epigenetic memories depending on microorganism nature. Constitutively associated transcription factors (TFs) include CCAAT enhancer binding protein beta (C/EBPb), purine rich DNA binding protein (PU.1), early growth response 2 (EGR2) and signal transducer and activator of transcription 1 (STAT1) while hypoxia-inducible factors (HIFs) and interferon regulatory factor 1 (IRF1) may stimulate iron acquisition in pro-inflammatory conditions. Mouse orthologous locus is generally conserved; chromatin patterns typify a de novo myelo-monocytic gene whose expression is tightly controlled by TFs Pu.1, C/ebps and Irf8; Irf3 and nuclear factor NF-kappa-B p 65 subunit (RelA) regulate expression in inflammatory conditions. Functional differences in the determinants identified at these orthologous loci imply that species-specific mechanisms control gene expression.

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“…SREBP1 expression is induced in MΦs upon inflammatory stimulation, which both promotes acute inflammatory responses (Im et al, 2011; Reboldi et al, 2014) and contributes to the resolution of the pro-inflammatory TLR4 signaling(Oishi et al, 2017). However, the reduction of CYP51A1 expression in response to LPS was observed in the absence of SREBP processing or SREBP2 expression, indicating that additional mechanisms must account for the early decreased expression of Cyp51A1 observed upon inflammatory stimulation.…”

Section: Discussionmentioning

confidence: 99%

Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages

et al. 2017

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SUMMARY Macrophages perform critical functions in both innate immunity and in cholesterol metabolism. Here we report that activation of toll-like receptor 4 (TLR-4) in macrophages causes lanosterol, the first sterol intermediate in the cholesterol biosynthetic pathway, to accumulate. This effect is due to type I interferon (IFN)-dependent histone deacetylase 1 (HDAC-1) transcriptional repression of lanosterol-14α-demethylase, the gene product of Cyp51A1. Lanosterol accumulation in macrophages, either due to treatment with ketoconazole or induced conditional disruption of Cyp51A1 in mouse MΦs in vitro, decreases IFNβ-mediated STAT1-STAT2 activation and IFNβ-stimulated gene expression. These effects translate into increased survival to endotoxemic shock by reducing cytokine secretion. Additionally, lanosterol accumulation increases membrane fluidity and ROS production thus potentiating phagocytosis and the ability to kill bacteria. This improves resistance of mice to Listeria monocytogenes infection by increasing bacterial clearance in the spleen and liver. Overall our data indicate that lanosterol is an endogenous selective regulator of macrophage immunity.

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SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism

Cited by 264 publications

References 46 publications

Liver X receptors link lipid metabolism and inflammation

Liver X receptors link lipid metabolism and inflammation

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages

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