Bmal1 integrates mitochondrial metabolism and macrophage activation

Alexander, R. S.; Liou, Yae-Huei; Knudsen, Nelson H.; Starost, Kyle A.; Xu, Cenke; Hyde, Alexander L.; Liu, Sihao; Jacobi, David; Liao, Nan‐Shih; Lee, Chih‐Hao

doi:10.7554/elife.54090

Cited by 91 publications

(98 citation statements)

References 58 publications

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“…The role of energy metabolism in osteoclasts is shown in Figure 5 . Osteoclasts during differentiation (developmental process) can be regarded as a subgroup of macrophages, and energy metabolism is closely related to the polarization of macrophages ( 135 , 136 ). Metabolic studies on peritoneal macrophages (RAW264.7) and bone marrow-derived macrophages (BMDM) indicated that lysine promotes the activation of M1 and M2, while tyrosine and phenylalanine have opposite effects ( 137 ).…”

Section: Regulators Of the Differentiation Of Macrophages Into Osteocmentioning

confidence: 99%

The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases

et al. 2021

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Osteoimmunity is involved in regulating the balance of bone remodeling and resorption, and is essential for maintaining normal bone morphology. The interaction between immune cells and osteoclasts in the bone marrow or joint cavity is the basis of osteoimmunity, in which the macrophage-osteoclast axis plays a vital role. Monocytes or tissue-specific macrophages (macrophages resident in tissues) are an important origin of osteoclasts in inflammatory and immune environment. Although there are many reports on macrophages and osteoclasts, there is still a lack of systematic reviews on the macrophage-osteoclast axis in osteoimmunity. Elucidating the role of the macrophage-osteoclast axis in osteoimmunity is of great significance for the research or treatment of bone damage caused by inflammation and immune diseases. In this article, we introduced in detail the concept of osteoimmunity and the mechanism and regulators of the differentiation of macrophages into osteoclasts. Furthermore, we described the role of the macrophage-osteoclast axis in typical bone damage caused by inflammation and immune diseases. These provide a clear knowledge framework for studying macrophages and osteoclasts in inflammatory and immune environments. And targeting the macrophage-osteoclast axis may be an effective strategy to treat bone damage caused by inflammation and immune diseases.

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Section: Regulators Of the Differentiation Of Macrophages Into Osteocmentioning

confidence: 99%

The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases

et al. 2021

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“…HIF-1 α has been shown to be stabilized by increased pyruvate levels [ 269 ], such as those that occur following PDC inhibition, or by increased succinate levels [ 270 ]. The circadian transcriptional regulator Bmal1, which can be induced by the hormone melatonin [ 271 ], decreases HIF-1 α stability and levels to increase mitochondrial oxidative metabolism [ 272 ]. In lung AECs, stabilization of HIF1- α was shown to cause ER stress and CHOP-mediated apoptosis [ 273 ].…”

Section: Molecular Mechanisms Through Which R-bhb Restores Redox Bmentioning

confidence: 99%

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Bradshaw

Seeds²,

Miller

et al. 2020

Oxidative Medicine and Cellular Longevity

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Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. During a virus-induced cytokine storm, metabolic flexibility is compromised due to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage, downregulate, or inactivate many enzymes of central metabolism including the pyruvate dehydrogenase complex (PDC). This leads to an energy and redox crisis that decreases B and T cell proliferation and results in increased cytokine production and cell death. It is hypothesized that a moderately high-fat diet together with exogenous ketone supplementation at the first signs of respiratory distress will increase mitochondrial metabolism by bypassing the block at PDC. R-BHB-mediated restoration of nucleotide coenzyme ratios and redox state should decrease ROS and RNS to blunt the innate immune response and the associated cytokine storm, allowing the proliferation of cells responsible for adaptive immunity. Limitations of the proposed therapy include the following: it is unknown if human immune and lung cell functions are enhanced by ketosis, the risk of ketoacidosis must be assessed prior to initiating treatment, and permissive dietary fat and carbohydrate levels for exogenous ketones to boost immune function are not yet established. The third limitation could be addressed by studies with influenza-infected mice. A clinical study is warranted where COVID-19 patients consume a permissive diet combined with ketone ester to raise blood ketone levels to 1 to 2 mM with measured outcomes of symptom severity, length of infection, and case fatality rate.

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“…Bmal1, a core gene in the body clock, regulates the liver’s biological rhythms. Importantly, it has been pointed out in the literature that the clock gene Bmal1 has crucial effect on macrophages in a variety of diseases, such as inflammatory and metabolic diseases ( Oishi et al, 2017 ; Alexander et al, 2020 ). Furthermore, inflammatory stimulant LPS can also suppress Bmal1 expression in the innate immune response of macrophages ( Curtis et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Bmal1 Regulates Macrophage Polarize Through Glycolytic Pathway in Alcoholic Liver Disease

Zhou

et al. 2021

Front. Pharmacol.

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Hepatic macrophages play a critical role in inflammation caused by alcohol feeding. During this process, variation of macrophage phenotypes triggers inflammatory responses in a variety of ways. Moreover, there is increasing evidence that Brain and Muscle Arnt-Like Protein-1 (Bmal1) is regarded as a key regulator of macrophage transformation. In our study, Bmal1 was detected to be low expressed in EtOH-fed mice tissue samples and ethanol-induced RAW264.7 cells. After hepatic specific overexpression of Bmal1, M1 macrophage markers were evidently down-regulated, while M2 markers were on the contrary, showing an upward trend. Furthermore, alcoholic liver lesions were also improved in alcohol feeding mice with overexpressed Bmal1. On this basis, we also found that the glycolytic pathway can regulate macrophage polarization. In vitro, blocking of glycolytic pathway can significantly inhibit M1-type polarization. Importantly, glycolysis levels were also restrained after Bmal1 overexpression. What’s more, Bmal1 exerts a negative regulatory effect on glycolysis by interacting with S100A9 protein. Further studies showed that the alleviation of alcoholic liver disease (ALD) by Bmal1 was associated with glycolytic pathway suppression and M1 macrophage polarization. In summary, we demonstrated that Bmal1 is a gene capable of relieving ALD, and this effect may provide new insights for altering macrophage phenotypes to regulate inflammatory responses in ALD.

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Bmal1 integrates mitochondrial metabolism and macrophage activation

Cited by 91 publications

References 58 publications

The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases

The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Bmal1 Regulates Macrophage Polarize Through Glycolytic Pathway in Alcoholic Liver Disease

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