Orphan Nuclear Receptor ERRα Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation

Yuk, Jae–Min; Kim, Tae Sung; Kim, Soo Yeon; Lee, Hyemi; Han, Jin-Tae; Dufour, Catherine R.; Kim, Jin‐Kyung; Jin, Hyo Sun; Yang, Chul–Su; Park, Ki-Sun; Lee, Chul‐Ho; Kim, Jin Man; Kweon, Gi Ryang; Choi, Hueng‐Sik; Vanacker, Jean‐Marc; Moore, David D.; Giguère, Vincent; Jo, Eun-Kyeong

doi:10.1016/j.immuni.2015.07.003

Cited by 106 publications

(105 citation statements)

References 49 publications

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“…ERRα transcriptionally regulates the expression of genes encoding energy metabolism regulators (28,30,31). To test whether ERRα could functionally phenocopy the role of MYC in mitochondrial respiration in osteoclasts, we measured mitochondrial respiration following RANKL stimulation using ERRα-deficient OCPs isolated from ERRα-null mice.…”

Section: Resultsmentioning

confidence: 99%

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

Bae

Lee

Mun

et al. 2017

Journal of Clinical Investigation

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101

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Section: Resultsmentioning

confidence: 99%

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

Bae

Lee

Mun

et al. 2017

Journal of Clinical Investigation

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101

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“…Immunoblotting was performed as described previously (22). For immunoblotting, cells were lysed in RIPA (10 mM Tris-HCl at pH 8, 1 mM EDTA, 140 mM NaCl, 0.1% SDS, 0.1% sodium deoxycholate, and 1% Triton X-100) and a protease inhibitor mixture (Roche).…”

Section: Immunoblottingmentioning

confidence: 99%

“…Briefly, total RNA from cells was isolated using TRIzol reagent (15596-026; Thermo Fisher Scientific) and used for synthesis of cDNA with Superscript II reverse transcriptase (Invitrogen). For semiquantitative RT-PCR reactions involved 30 cycles of annealing, extension, and denaturation as described previously (22). Reactions were run on a Veriti 96-Well Thermal Cycler (Thermo Fisher).…”

Section: Immunoblottingmentioning

confidence: 99%

PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism

Kim

Lee

Kim

et al. 2017

The Journal of Immunology

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127

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The role of peroxisome proliferator–activated receptor α (PPAR-α) in innate host defense is largely unknown. In this study, we show that PPAR-α is essential for antimycobacterial responses via activation of transcription factor EB (TFEB) transcription and inhibition of lipid body formation. PPAR-α deficiency resulted in an increased bacterial load and exaggerated inflammatory responses during mycobacterial infection. PPAR-α agonists promoted autophagy, lysosomal biogenesis, phagosomal maturation, and antimicrobial defense against Mycobacterium tuberculosis or M. bovis bacillus Calmette–Guérin. PPAR-α agonists regulated multiple genes involved in autophagy and lysosomal biogenesis, including Lamp2, Rab7, and Tfeb in bone marrow–derived macrophages. Silencing of TFEB reduced phagosomal maturation and antimicrobial responses, but increased macrophage inflammatory responses during mycobacterial infection. Moreover, PPAR-α activation promoted lipid catabolism and fatty acid β-oxidation in macrophages during mycobacterial infection. Taken together, our data indicate that PPAR-α mediates antimicrobial responses to mycobacterial infection by inducing TFEB and lipid catabolism.

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“…A recent interesting finding concerns a connection between the orphan nuclear receptor ERRα and a critical negative regulator of inflammation, the deubiquitinating enzyme A20 (Yuk et al, 2015). ERRα is a well-known regulator of energy metabolism and mitochondrial biogenesis (Villena and Kralli, 2008).…”

Section: Negative Control Of Metabolic Reprogramming In M1 Macrophagementioning

confidence: 99%

“…A20 has been shown to be a key inhibitor of inflammation in multiple human diseases, recent notable examples being to prevent rheumatoid arthritis and also asthma (Vande Walle et al, 2014;Schuijs et al, 2015). Yuk et al (2015) have shown that ERRα directly binds to the A20 gene promoter and increases its expression. ERRα-deficient mice are highly susceptible to LPS-induced septic shock and also have elevated glycolysis and decreased oxidative phosphorylation.…”

Section: Negative Control Of Metabolic Reprogramming In M1 Macrophagementioning

confidence: 99%

Immunometabolism governs dendritic cell and macrophage function

O’Neill¹,

Pearce²

2016

J Cell Biol

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The main challenge of metabolic pathways has always been their complexity. This stems from the number of metabolites (which intracellularly can run into the thousands), their chemical complexity, and the sophisticated regulation of the enzymes that control them. Recent discoveries on the role of metabolic pathways in immune cell function have brought the burgeoning area of immunometabolism to the forefront for many immunologists. In this review, we will discuss recent findings in macrophages and DCs, critical cell types for both innate and adaptive immunity. A primary goal for immunologists is to uncover the molecular players in processes that provide a detailed account of how the effector functions of immune cells are controlled. These processes become dysregulated in disease. The analysis of metabolic reprogramming in macrophages and DCs provides new insights into how these cells perform their functions, including cytokine production, phagocytosis, or antigen presentation. The somewhat surprising finding is that metabolic processes such as glycolysis, the Krebs cycle, and fatty acid metabolism have highly specific effects on macrophage and DC function. The manipulation of these pathways can dramatically alter the functioning of these cells in specific ways, rather than simply being involved in energy generation or general biosynthesis. Metabolic reprogramming as a phenomenon is therefore joining other key immunoregulatory events that govern the nature of the immune response, both in health and disease. What is metabolic reprogramming?A simple view of metabolic reprogramming is that it reflects the responses of cells to critical changes in the environment. For example, under normoxic conditions, cells can use oxidative phosphorylation (OXP HOS) to generate ATP. Critical components of the electron transport chain (ETC) use NADH and FADH generated as a result of reactions in the Krebs cycle, which in turn is fueled by glucose, fatty acids, and glutamine. In contrast, when O 2 tensions are low, cells can to a greater or lesser degree generate ATP through glycolysis and independently of OXP HOS, but this pathway is highly dependent on glucose as a sole fuel source. The core metabolic pathways are essential for interchanging carbons between sugars, fatty acids, nucleic acids, and proteins, and therefore, metabolic flexibility can play a critical role as prevailing nutrient and oxygen conditions change. This can be of great importance if a cell is faced with differing functional demands. A critical point from the perspective of this review is that recent work has emphasized the fact that changes in key metabolic regulatory events in immune cells can be initiated not only by nutrient and oxygen conditions, but also in reprogramming events downstream of ligation of pattern recognition receptors (PRRs), cytokine receptors, and/or Ag receptors (and likely other receptors). Thus, in immune cells, there is the potential for metabolic changes to occur in response to instructional signals received from other cells or from ch...

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Orphan Nuclear Receptor ERRα Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation

Cited by 106 publications

References 49 publications

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism

Immunometabolism governs dendritic cell and macrophage function

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