MicroRNA-252 and FoxO regulate inflammaging through dual inhibition on Dawdle/Acticin of TGF-β pathway in Drosophila
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PROVIDER: PRJNA512241 | ENA |
REPOSITORIES: ENA
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Project description:The abstract for the manuscript Inflammaging refers to low-grade, chronically activated innate immunity that negatively impacts adult survival. However, little is known about the intrinsic signaling pathway that upregulates innate immune genes during aging. Here using Drosophila melanogaster, we profile the microRNA targetomes in young and aged animals, and reveal Dawdle (Daw), an activin-like ligand of the TGF-beta pathway, as a physiological target of microRNA-252 (miR-252). We show that miR-252 cooperates with the transcriptional regulation of Daw by Forkhead box O (FoxO), a conserved transcriptional factor implicated in aging, at the post-transcriptional levels. Unopposed Daw triggers hyper activation of innate immune genes coupled with a catastrophic decline in organismal survival. Single-cell sequencing analysis describes a non-cell autonomous regulation between Daw and the induction of innate immune genes in the muscle. We further determine the downstream cascade by which Daw signaling leads to increased Kenny /IKKgamma protein, which in turn activates Relish/NF-kappaB protein and consequentially upregulation of innate immune genes. Finally, while aging leads to a decline in FoxO activity, transgenic increase of miR-252 and FoxO pathway factors in wild-type Drosophila extends lifespan and mitigates the induction of innate immune genes in aging. Together, we propose that miR-252 and FoxO repress inflammaging by cooperative inhibition of Daw mediated TGF-beta pathway.
2021-01-01 | GSE142655 | GEO
Project description:Innate immunity is a highly reactive response aiming at clearing pathogens. Abnormal induction of innate immune genes can lead to deleterious consequences to the host. However, little is known about the intrinsic signaling pathway that prohibits constitutive activation of innate immunity. Here using fruit flies, we profile the microRNA targetomes in young and aged animals. We demonstrate FoxO, and miR-252 inhibit spontaneous induction of innate immunity by repressing Daw. We further determine the signaling cascade by which Daw causes the reduction of Atg8a-mediated selective autophagy on kenny protein, which in turn activates Relish protein and consequential upregulation of innate immune genes. Finally, while aging leads to a decline in FOXO signaling activity concomitant with a progressive induction of innate immune genes, transgenic increase of FoxO, miR-252, and Atg8a in wild-type Drosophila promotes longevity and mitigates the expression of age-onset innate immune genes. Together, we propose that FoxO and miR-252 define a pro-survival mechanism by inhibiting constitutive innate immunity.
2018-12-31 | GSE124504 | GEO
Project description:microRNA-252 and FoxO repress inflammaging by a dual inhibitory mechanism on Dawdle mediated TGF-β pathway in Drosophila muscle
| PRJNA597884 | ENA
Project description:Inflammaging refers to low-grade, chronically activated innate immunity that has deleterious effects on healthy lifespan. However, little is known about the intrinsic signaling pathway that elicits innate immune genes during aging. Here, using Drosophila melanogaster, we profile the microRNA targetomes in young and aged animals, and reveal Dawdle, an activin-like ligand of the TGF-β pathway, as a physiological target of microRNA-252. We show that microRNA-252 cooperates with Forkhead box O, a conserved transcriptional factor implicated in aging, to repress Dawdle. Unopposed Dawdle triggers hyperactivation of innate immune genes coupled with a decline in organismal survival. Using adult muscle tissues, single-cell sequencing analysis describes that Dawdle and its downstream innate immune genes are expressed in distinct cell types, suggesting a cell nonautonomous mode of regulation. We further determine the genetic cascade by which Dawdle signaling leads to increased Kenny/IKKγ protein, which in turn activates Relish/NF-κB protein and consequentially innate immune genes. Finally, transgenic increase of microRNA-252 and Forkhead box O pathway factors in wild-type Drosophila extends lifespan and mitigates the induction of innate immune genes in aging. Together, we propose that microRNA-252 and Forkhead box O promote healthy longevity by cooperative inhibition on Dawdle-mediated inflammaging.
| S-EPMC9208648 | biostudies-literature
Project description:Post-embryonic development of the nematode C. elegans is governed by nutrient availability. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This “L1 arrest” (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. daf-16/FOXO had overlapping but distinct effects on gene expression in L1 arrest compared to daf-2/InsR adults. Notably, dbl-1/TGF-β, a ligand for the Sma/Mab pathway, and daf-36, which encodes an upstream component of the daf-12/NHR steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β and daf-36. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype, and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.
2016-05-27 | GSE69329 | GEO
Project description:Aerococcaceae bacterium zg-252 isolate:zg-252 Genome sequencing
| PRJNA685286 | ENA
Project description:The study objectives were to 1) determine mesenchymal stem cell (MSC) surface expression of major histocompatibility complex (MHC) class I and transcriptome-wide gene expression changes following IL-1β + TGF-β2 dual licensing and 2) evaluate if IL-1β + TGF-β2 dual licensed MSCs had greater ability to positively modulate tenocyte function compared to naïve MSCs.
2024-02-25 | GSE256139 | GEO
Project description:Bradyrhizobium elkanii USDA 252 genome sequencing
| PRJNA1115712 | ENA
Project description:Aerococcaceae bacterium zg-252 overview
| PRJNA1150713 | ENA
Project description:Aging is accompanied by chronic, low-grade systemic inflammation, termed inflammaging, a main driver of age-associated diseases. Such sterile inflammation is typically characterized by elevated levels of pro-inflammatory mediators, such as cytokines and reactive oxygen species causing organ damage. Lipid mediators play important roles in the fine-tuning of both the promotion and the resolution of inflammation. Yet, it remains unclear how lipid mediators fit within the concept of inflammaging and how their biosynthesis and function is affected by aging. Here, we provide comprehensive signature profiles of inflammatory markers in organs afflicted with inflammation of young and old C57BL/6 mice. We reveal an organ-specific footprint of inflammation-related cytokines, chemokines and lipid mediators, which are distinctively affected by aging. While some organs are characterized by a pronounced pro-inflammatory microenvironment and impaired resolution during aging, others display elevated levels of pro-resolving mediators or an overall decrease in inflammatory signaling. Our results demonstrate that it proves difficult to establish a unifying concept for alterations of immunomodulatory mediators as consequence of aging and that organ specificity needs to be considered. Moreover, our data imply that inclusion of lipid mediators into the concept of inflammaging provides a comprehensive tool to characterize the inflammatory microenvironment during aging on a broader and yet, more detailed scope.
2021-03-22 | PXD024356 | Pride