FoxO3 Modulates LPS-Activated Hepatic Inflammation in Turbot (Scophthalmus maximus L.)

Pan, Mingzhu; Liu, Jiahuan; Huang, Daochao; Guo, Yan‐Lin; Luo, Kai; Yang, Mingfang; Gao, Weihua; Xu, Qiaoqing; Zhang, Wenbing; Mai, Kangsen

doi:10.3389/fimmu.2021.679704

Cited by 7 publications

(3 citation statements)

References 60 publications

(76 reference statements)

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“…In contrast, FoxO3 and FoxO4 in macrophages and endothelial cells have been shown to be protective against inflammation and atherogenesis. 64–68 Together, these data demonstrate the multifaceted roles of FoxO family members and how they can vary in different disease states. Therefore, the proatherogenic nature of the triple deletion mice is likely a composite result of a dysregulation of pushing-and-pulling effects between different FoxO family members.…”

Section: Discussionmentioning

confidence: 82%

Loss of Macrophage mTORC2 Drives Atherosclerosis via FoxO1 and IL-1β Signaling

Zhang

Evans²,

Chen³

et al. 2023

Circulation Research

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Background: The mTOR (mechanistic target of rapamycin) pathway is a complex signaling cascade that regulates cellular growth, proliferation, metabolism, and survival. Although activation of mTOR signaling has been linked to atherosclerosis, its direct role in lesion progression and in plaque macrophages remains poorly understood. We previously demonstrated that mTORC1 (mTOR complex 1) activation promotes atherogenesis through inhibition of autophagy and increased apoptosis in macrophages. Methods: Using macrophage-specific Rictor- and mTOR-deficient mice, we now dissect the distinct functions of mTORC2 pathways in atherogenesis. Results: In contrast to the atheroprotective effect seen with blockade of macrophage mTORC1, macrophage-specific mTORC2-deficient mice exhibit an atherogenic phenotype, with larger, more complex lesions and increased cell death. In cultured macrophages, we show that mTORC2 signaling inhibits the FoxO1 (forkhead box protein O1) transcription factor, leading to suppression of proinflammatory pathways, especially the inflammasome/IL (interleukin)-1β response, a key mediator of vascular inflammation and atherosclerosis. In addition, administration of FoxO1 inhibitors efficiently rescued the proinflammatory response caused by mTORC2 deficiency both in vitro and in vivo. Interestingly, collective deletion of macrophage mTOR, which ablates mTORC1- and mTORC2-dependent pathways, leads to minimal change in plaque size or complexity, reflecting the balanced yet opposing roles of these signaling arms. Conclusions: Our data provide the first mechanistic details of macrophage mTOR signaling in atherosclerosis and suggest that therapeutic measures aimed at modulating mTOR need to account for its dichotomous functions.

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Section: Discussionmentioning

confidence: 82%

Loss of Macrophage mTORC2 Drives Atherosclerosis via FoxO1 and IL-1β Signaling

Zhang

Evans²,

Chen³

et al. 2023

Circulation Research

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“…In human, Drosophila, and shrimp ( Marsupenaeus japonicus ), FoxO signaling could activate the production of antimicrobial peptides (AMPs) to fight pathogen infections, where the regulation was evolutionarily conserved (Becker et al, 2010; Fink et al, 2016; Li et al, 2021). Furthermore, FOXO members have been found to be important in aquaculture fish species after bacterial infections, including largemouth bass ( Micropterus salmoides ) (Zhou et al, 2021), turbot ( Scophthalmus maximus ) (Pan et al, 2021), and channel catfish ( Ictalurus punctatus ) (Gao et al, 2019). For instance, FoxO3 was found to modulate LPS-activated hepatic inflammation in turbot.…”

Section: Discussionmentioning

confidence: 99%

m6A methylation dynamically participates in the immune response againstVibrio anguillarumin half-smooth tongue sole (Cynoglossus semilaevis)

Tan,

Wang,

Han

et al. 2024

Preprint

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N6-methyladenosine (m6A) is the most prevalent RNA modification and a multifaceted regulator capable of affecting various aspects of mRNA metabolism, thereby playing important roles in numerous physiological processes. However, it is still unknown whether, when, and to what extent m6A modulation are implicated in the immune response of an economically important aquaculture fish, half-smooth tongue sole (Cynoglossus semilaevis). Herein, we systematically profiled and characterized the m6A epitranscriptome and transcriptome inC. semilaevisafter the infection ofVibrio anguillarum, a serious threat to the aquaculture industry. We demonstrated that m6A could be modulated as early as 4-hour post infection (hpi), and the overall intensity of m6A methylation was enhanced following infection. Both conservative and novel motifs were uncovered from the m6A modification sites. Furthermore, differentially m6A methylated genes (DMGs) and differentially expressed genes (DEGs) were identified, and functional enrichment revealed multiple immune-related pathways, especially the FoxO signaling pathway which showed significance in every comparison. Joint analysis highlighted the remarkedly dynamic role of m6A on gene expression, i.e. early on, m6A mainly prioritized the down-regulation of specific genes, and later, it switched gears to promote expression of another set of genes. Moreover, key immune-related genes, includingpdp1,rgs5l, andplk2b, were identified. To our limited knowledge, this is the first study comprehensively characterizing the global m6A atlas in aquaculture fish species. The presented results provide new insights into the dynamics of m6A modifications in the transcriptome of the half-smooth tongue sole following bacterial infection. Further studies are warranted to elucidate the functional significance of these changes and to understand how they affect specific biological processes.

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“…FoxO3 exerts vital effects on the fish’s innate immune response to pathogens [ 64 ]. In LPS-stimulated turbot, diminished FoxO3 significantly promoted the expression of proinflammatory cytokines (such as TNF-α and IL-6), while overexpressed FoxO3 attenuated the LPS-induced hepatic inflammation [ 65 ]. In line with this, FoxO3 was found significantly down- and up-regulated at invaded and recovering stages in our study, respectively, which suggests the immune defense via inflammatory response during pathogenic infection, and the protection against excessive inflammation-induced tissue damage during host recovery.…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Transcriptome and Metabolome Reveals Distinct Responses of Pelteobagrus fulvidraco against Aeromonas veronii Infection at Invaded and Recovering Stage

Ning

Peng

Tang

et al. 2022

IJMS

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Yellow catfish (Pelteobagrus fulvidraco) is an important aquaculture fish susceptible to Aeromonas veronii infection, which causes acute death resulting in huge economic losses. Understanding the molecular processes of host immune defense is indispensable to disease control. Here, we conducted the integrated and comparative analyses of the transcriptome and metabolome of yellow catfish in response to A. veronii infection at the invaded stage and recovering stage. The crosstalk between A. veronii-induced genes and metabolites uncovered the key biomarkers and pathways that strongest contribute to different response strategies used by yellow catfish at corresponding defense stages. We found that at the A. veronii invading stage, the immune defense was strengthened by synthesizing lipids with energy consumption to repair the skin defense line and accumulate lipid droplets promoting intracellular defense line; triggering an inflammatory response by elevating cytokine IL-6, IL-10 and IL-1β following PAMP-elicited mitochondrial signaling, which was enhanced by ROS produced by impaired mitochondria; and activating apoptosis by up-regulating caspase 3, 7 and 8 and Prostaglandin F1α, meanwhile down-regulating FoxO3 and BCL6. Apoptosis was further potentiated via oxidative stress caused by mitochondrial dysfunction and exceeding inflammatory response. Additionally, cell cycle arrest was observed. At the fish recovering stage, survival strategies including sugar catabolism with D-mannose decreasing; energy generation through the TCA cycle and Oxidative phosphorylation pathways; antioxidant protection by enhancing Glutathione (oxidized), Anserine, and α-ketoglutarate; cell proliferation by inducing Cyclin G2 and CDKN1B; and autophagy initiated by FoxO3, ATG8 and ATP6V1A were highlighted. This study provides a comprehensive picture of yellow catfish coping with A. veronii infection, which adds new insights for deciphering molecular mechanisms underlying fish immunity and developing stage-specific disease control techniques in aquaculture.

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FoxO3 Modulates LPS-Activated Hepatic Inflammation in Turbot (Scophthalmus maximus L.)

Cited by 7 publications

References 60 publications

Loss of Macrophage mTORC2 Drives Atherosclerosis via FoxO1 and IL-1β Signaling

Loss of Macrophage mTORC2 Drives Atherosclerosis via FoxO1 and IL-1β Signaling

m6A methylation dynamically participates in the immune response againstVibrio anguillarumin half-smooth tongue sole (Cynoglossus semilaevis)

Integrated Analysis of Transcriptome and Metabolome Reveals Distinct Responses of Pelteobagrus fulvidraco against Aeromonas veronii Infection at Invaded and Recovering Stage

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