PERK is a critical metabolic hub for immunosuppressive function in macrophages

Raines, Lydia; Zhao, Haoxin; Wang, Yuzhu; Chen, Heng-Yi; Gallart-Ayala, Héctor; Hsueh, Pei-Chun; Cao, Wei; Koh, Yeojung; Alamonte-Loya, Ana; Liu, Po–Tsun; Ivanišević, Julijana; Lio, Chan-Wang Jerry; Ho, Ping‐Chih; Huang, Stanley Ching-Cheng

doi:10.1038/s41590-022-01145-x

Cited by 99 publications

(82 citation statements)

References 65 publications

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“…As the resident macrophages in the brain, microglia exert a significant effect on the inflammatory response [4]. Microglia activation can be divided into the proinflammatory M1 polarization state and the anti-inflammatory M2 stimulation status, which are related to the delivery of proinflammatory and anti-inflammatory cytokines, respectively [5,6]. Several types of research have shown that proinflammatory cytokines including tumor necrosis element-α (TNF-α) from microglia within the hippocampus exert a pathogenic effect on cognitive disorders [7].…”

Section: Introductionmentioning

confidence: 99%

Impact of Dexamethasone Preconditioning on Prevention of Development of Cognitive Impairment following Acute Inflammation

Cheng

Song

Liu

et al. 2022

Contrast Media & Molecular Imaging

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To assess the preventive role of dexamethasone (Dex) in the development of neuroinflammation and concomitant neurocognitive disorders following acute inflammation. C57BL6 mice were fallen into the sham group, ischemia-reperfusion (I/R) group, and I/R + Dex group randomly. In the end, behavioral alterations were assessed with the Morris water maze (MWM) test, passive avoidance test (PAT), and open field test (OFT). The serum levels of IL-1β and TNF-α were detected by ELISA. Immunofluorescence was adopted to observe the NF-kB expression in the hippocampus. In addition, TLR4, NF-kB, CD68, and CD206 were examined by Western blot. The cognitive ability of mice can be impaired by tourniquet-induced acute inflammation, and these changes were prevented by Dex. Compared to the I/R group, Dex pretreatment could decrease levels of IL-1β and TNF-α proteins in serum. Besides, Dex preconditioning significantly decreased the utterance of NF-kB immunoreactive cells and TLR4, NF-kB, and CD68 overexpression in the hippocampus. Dex partly through inhibiting microglia transformation to the M1 polarization state and inactivating the TLR4/NF-kB pathway attenuates the cognitive disorders in mice.

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Section: Introductionmentioning

confidence: 99%

Impact of Dexamethasone Preconditioning on Prevention of Development of Cognitive Impairment following Acute Inflammation

Cheng

Song

Liu

et al. 2022

Contrast Media & Molecular Imaging

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“…Our results showed that higher expression of PSAT1 in cancer cells may explain higher expression of EVs by cancer cells than normal cells. Serine-related metabolic pathways enhance cancer cell proliferation (32)(33)(34). HCT116 cells is highly dependent on de novo biosynthesis of serine and glycine (33,35).…”

Section: Discussionmentioning

confidence: 99%

Aberrant regulation of serine metabolism drives extracellular vesicle release and cancer progression

Nakayama¹,

Urabe²,

Ito³

et al. 2022

Preprint

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Cancer cells secrete extracellular vesicles (EVs) to regulate cells in the tumor microenvironment for their own benefit to grow and survive in the patient’s body. Although emerging evidence has demonstrated the molecular mechanisms of EV release, regulating cancer-specific EV secretion remains challenging. In this study, we applied a microRNA (miRNA) library to reveal the universal mechanisms of EV secretion in cancer cells. Here, we identified miR-891b and its direct target gene, phospho-aminotransferase 1 (PSAT1), which promotes EV secretion through the serine synthesis pathway. Inhibition of PSAT1 affected EV secretion in multiple types of cancer, suggesting that the miR-891b/PSAT1 axis shares a common mechanism of cancer EV secretion. Interestingly, PSAT1 also controlled cancer metastasis via EV secretion. Our data provide insights into the PSAT1-controlled EV secretion mechanism and its potential as a therapeutic target in multi types of cancer.

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“…It has been reported that JMJD3 contributes to decreased H3K27 methylation levels and increases the transcriptional activity of M2 marker genes ( 60 ). Meanwhile, it was found that activated PERK promotes serine biosynthesis through the downstream transcription factor ATF-4, which leads to enhanced mitochondrial function and α-ketoglutarate production required for JMJD3-dependent epigenetic modification, thus promoting mitochondrial respiration and lipid oxidation in M2 macrophages ( 61 ). Furthermore, it has been demonstrated that the transcription factor CTCF recruits histone acetyltransferase E1A binding protein p300 to promoter regions by binding to downstream acting targets, thereby enhancing histone acetylation and gene transcription and promoting M2 polarization of TAM ( 62 ).…”

Section: Metabolism-related Signaling Pathways In Macrophage Polariza...mentioning

confidence: 99%

Metabolic Reprogramming Induces Macrophage Polarization in the Tumor Microenvironment

Wang

Liu

et al. 2022

Front. Immunol.

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Macrophages are one of the most important cells in the innate immune system, they are converted into two distinct subtypes with completely different molecular phenotypes and functional features under different stimuli of the microenvironment: M1 macrophages induced by IFN-γ/lipopolysaccharides(LPS) and M2 macrophages induced by IL-4/IL-10/IL-13. Tumor-associated macrophages (TAMs) differentiate from macrophages through various factors in the tumor microenvironment (TME). TAMs have the phenotype and function of M2 macrophages and are capable of secreting multiple cytokines to promote tumor progression. Both tumor cells and macrophages can meet the energy needs for rapid cell growth and proliferation through metabolic reprogramming, so a comprehensive understanding of pro-tumor and antitumor metabolic switches in TAM is essential to understanding immune escape mechanisms. This paper focuses on the functions of relevant signaling pathways and cytokines during macrophage polarization and metabolic reprogramming, and briefly discusses the effects of different microenvironments and macrophage pathogenicity, in addition to describing the research progress of inhibitory drugs for certain metabolic and polarized signaling pathways.

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PERK is a critical metabolic hub for immunosuppressive function in macrophages

Cited by 99 publications

References 65 publications

Impact of Dexamethasone Preconditioning on Prevention of Development of Cognitive Impairment following Acute Inflammation

Impact of Dexamethasone Preconditioning on Prevention of Development of Cognitive Impairment following Acute Inflammation

Aberrant regulation of serine metabolism drives extracellular vesicle release and cancer progression

Metabolic Reprogramming Induces Macrophage Polarization in the Tumor Microenvironment

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