SIRT1-Dependent Upregulation of BDNF in Human Microglia Challenged with Aβ: An Early but Transient Response Rescued by Melatonin

Caruso, Grazia Ilaria; Spampinato, Simona Federica; Costantino, Giuseppe; Merlo, Sara; Sortino, Maria Angela

doi:10.3390/biomedicines9050466

Cited by 24 publications

(14 citation statements)

References 104 publications

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“…The SIRT1 activity was detected in accordance with the previous research 27 . The 350 μg extracted proteins were diluted into 500 μl volume using M‐PER lysis buffer, followed by 24 h‐incubation with 2 μg anti‐SIRT1 (1:2000, ab92506; Abcam) at 4°C and then 20 μl protein A/G PLUS‐agarose beads (Sc‐2002; Santa Cruz Biotechnologies, Santa Cruz, CA, USA) at 4°C overnight.…”

Section: Methodsmentioning

confidence: 99%

Mechanism of chlorogenic acid in alveolar macrophage polarization in Klebsiella pneumoniae-induced pneumonia

Tan

Yang

et al. 2021

Journal of Leukocyte Biology

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Chlorogenic acid (CA) has been discovered to regulate macrophage polarization in pneumonia. This study aims to analyze the functional mechanism of CA in alveolar macrophage (AM) polarization and provide a theoretical basis for treatment of Klebsiella pneumoniae (Kp)-induced pneumonia. Mice were infected with Kp, and treated with CA and silent information regulator 1 (SIRT1) inhibitor (Selisistat). Mouse survival rate was recorded and bacterial burden was detected. AM polarization and pathologic change of lung tissues were evaluated. Expressions of SIRT1 and HMGB1 and cytokine levels were detected. MH-S cells were infected with Kp to establish the pneumonia cell model, followed by transfection of si-SIRT1 and HMGB1 overexpression vector. The HMGB1 expression in the nucleus and cytoplasm was detected. HMGB1 subcellular localization and HMGB1 acetylation level were detected. Kp led to high death rates, SIRT down-regulation and increases in inflammatory factor level and bacterial burden, and promoted M1 polarization. CA treatment improved mouse survival rate and promoted M2 polarization and SIRT1 expression. SIRT1 decreased HMGB1 acetylation level to inhibit nuclear to the cytoplasm translocation. Silencing SIRT1 or HMGB1 overexpression reversed the effect of CA on Kp-induced pneumonia. Overall, CA activated SIRT1 to inhibit HMGB1 acetylation level and nuclear translocation, thereby promoting M2 polarization in AMs and alleviating Kp-induced pneumonia.

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Section: Methodsmentioning

confidence: 99%

Mechanism of chlorogenic acid in alveolar macrophage polarization in Klebsiella pneumoniae-induced pneumonia

Tan

Yang

et al. 2021

Journal of Leukocyte Biology

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“…Downstream signaling that is inhibited by melatonin can concern different pathway branches, in particular, the phosphorylation of Akt, mTOR [ 37 , 40 ], and the stress kinases JNK and p38 [ 37 , 40 ]; the prevention of NADPH oxidase activation/assembly [ 38 , 40 , 41 ]; and the prevention of caspase-3 cleavage [ 35 , 36 , 42 ]. As a common feature that is observed throughout practically all pertinent studies, the suppression of NF-κB activation, which was often accompanied by Nrf2 upregulation, reflects the anti-inflammatory and antioxidant actions of melatonin in microglia [ 26 , 32 , 36 , 38 , 39 , 43 , 44 , 45 , 46 , 47 , 48 ]. Conversely, the suppression of melatonin secretion by sleep deprivation enhanced microglia activation, which was evident from proinflammatory traits such as NF-κB activation, JNK phosphorylation, the upregulation of NADPH oxidases 1, 2, and 4, and the release of proinflammatory cytokines [ 49 ].…”

Section: Melatonin Suppresses Proinflammatory and Favors Anti-inflammatory Signalingmentioning

confidence: 99%

“…Within this limited field, the upregulation of IL-10, IL-19, and TGFβ have been reported [ 53 ], but data on IL-4, IL-13, and various other anti-inflammatory factors are widely missing. The upregulation of BDNF (brain-derived neurotrophic factor) in microglia by melatonin [ 42 , 48 ] may be taken as a hint for a melatonin-directed M2 function that exceeds the suppression of inflammation that concerns proliferation and remodeling phases after injury, as typical for the M2b and M2c subtypes.…”

Section: Melatonin Suppresses Proinflammatory and Favors Anti-inflammatory Signalingmentioning

confidence: 99%

“…This latter role of SIRT1 is also plausible with regard to its HMGB1-deacetylating activity since acetylation of this alarmin is required for release [ 115 , 116 ]. In Aβ 42 -treated HMC3 cells, a human microglial cell line, melatonin was recently shown to not only prevent NF-κB nuclear translocation, but to also cause prolonged upregulations of SIRT1 and BDNF (brain-derived neurotrophic factor) [ 48 ]. Notably, BDNF is a factor released by M2 microglia [ 9 ].…”

Section: Melatonin’s Actions Via Sirtuins As Related To Microgliamentioning

confidence: 99%

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Melatonin and Microglia

Hardeland

2021

IJMS

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Melatonin interacts in multiple ways with microglia, both directly and, via routes of crosstalk with astrocytes and neurons, indirectly. These effects of melatonin are of relevance in terms of antioxidative protection, not only concerning free-radical detoxification, but also in prevention of processes that cause, promote, or propagate oxidative stress and neurodegeneration, such as overexcitation, toxicological insults, viral and bacterial infections, and sterile inflammation of different grades. The immunological interplay in the CNS, with microglia playing a central role, is of high complexity and includes signaling toward endothelial cells and other leukocytes by cytokines, chemokines, nitric oxide, and eikosanoids. Melatonin interferes with these processes in multiple signaling routes and steps. In addition to canonical signal transduction by MT1 and MT2 melatonin receptors, secondary and tertiary signaling is of relevance and has to be considered, e.g., via the upregulation of sirtuins and the modulation of pro- and anti-inflammatory microRNAs. Many details concerning the modulation of macrophage functionality by melatonin are obviously also applicable to microglial cells. Of particular interest is the polarization toward M2 subtypes instead of M1, i.e., in favor of being anti-inflammatory at the expense of proinflammatory activities, which is well-documented in macrophages but also applies to microglia.

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“…Cell level of NAD + is an important indicator of cell energy state [ 90 ]. Grazia Ilaria Caruso et al found that Aβ can up-regulate the expression of SRIT1 in the nucleus of human microglia cell line HMC3 and activate the enzyme activity of SIRT1 [ 89 ]. Lactate is not only a metabolic waste; glycolysis-derived lactate was identified as a substrate for histone lactonization [ 122 ] and Rui-Yuan Pan et al found increased histone lactonization in microglia adjacent to 5XFAD mouse plaques.…”

Section: Aβ and Tau As A Regulator Of Microglia Metabolism Reprogrammingmentioning

confidence: 99%

Aβ and Tau Regulate Microglia Metabolism via Exosomes in Alzheimer’s Disease

et al. 2022

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One of the most striking hallmarks shared by various neurodegenerative diseases, including Alzheimer’s disease (AD), is microglia-mediated neuroinflammation. The main pathological features of AD are extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles. The crosstalk between microglia and neurons helps maintain brain homeostasis, and the metabolic phenotype of microglia determines its polarizing phenotype. There are currently many research and development efforts to provide disease-modifying therapies for AD treatment. The main targets are Aβ and tau, but whether there is a causal relationship between neurodegenerative proteins, including Aβ oligomer and tau oligomer, and regulation of microglia metabolism in neuroinflammation is still controversial. Currently, the accumulation of Aβ and tau by exosomes or other means of propagation is proposed as a regulator in neurological disorders, leading to metabolic disorders of microglia that can play a key role in the regulation of immune cells. In this review, we propose that the accumulation of Aβ oligomer and tau oligomer can propagate to adjacent microglia through exosomes and change the neuroinflammatory microenvironment by microglia metabolic reprogramming. Clarifying the relationship between harmful proteins and microglia metabolism will help people to better understand the mechanism of crosstalk between neurons and microglia, and provide new ideas for the development of AD drugs.

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SIRT1-Dependent Upregulation of BDNF in Human Microglia Challenged with Aβ: An Early but Transient Response Rescued by Melatonin

Cited by 24 publications

References 104 publications

Mechanism of chlorogenic acid in alveolar macrophage polarization in Klebsiella pneumoniae-induced pneumonia

Mechanism of chlorogenic acid in alveolar macrophage polarization in Klebsiella pneumoniae-induced pneumonia

Melatonin and Microglia

Aβ and Tau Regulate Microglia Metabolism via Exosomes in Alzheimer’s Disease

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