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MicroRNA-252 and FoxO repress inflammaging by a dual inhibitory mechanism on Dawdle mediated TGF-β pathway in Drosophila muscle

ABSTRACT: 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.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE142655 | GEO | 2021/01/01

REPOSITORIES: GEO

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microRNA-252 and FoxO regulate inflammaging through dual inhibition on Dawdle/Acticin of TGF-β pathway in Drosophila

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

microRNA-252 and FoxO regulate inflammaging through dual inhibition on Dawdle/Acticin of TGF-β pathway in Drosophila

Project description:microRNA-252 and FoxO regulate inflammaging through dual inhibition on Dawdle/Acticin of TGF-β pathway in Drosophila

| PRJNA512241 | ENA

microRNA-252 and FoxO repress inflammaging by a dual inhibitory mechanism on Dawdle mediated TGF-β pathway in Drosophila muscle

Project description:microRNA-252 and FoxO repress inflammaging by a dual inhibitory mechanism on Dawdle mediated TGF-β pathway in Drosophila muscle

| PRJNA597884 | ENA

TXNRD1 drives innate immune response in senescent cells and promotes age-associated inflammation

Project description:Sterile inflammation, also known as inflammaging, is a hallmark of tissue ageing. Cellular senescence contributes to tissue aging in part through secretion of proinflammatory factors known as senescence-associated secretory phenotype (SASP). Thioredoxin reductase 1 (TXNRD1) genetic variability is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living, and physical performance at old age. TXNRD1 role in regulating tissue ageing has been attributed to its enzymatic role in regulating cellular redox. Here we show that TXNRD1 drives SASP and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragment and interacts with cGAS in a senescence status dependent manner. TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 and its interaction with cGAS is necessary for the SASP. TXNRD1 is required for both the tumor-promoting and immune-surveillance functions of senescent cells, which are mediated by SASP in vivo in mouse models. Treatment of aged mice with an TXNRD1 inhibitor that disrupts its interaction with cGAS, but not an inhibitor of its enzymatic activity, downregulated inflammaging in several tissues. In summary, our results report TXNRD1 promotes inflammaging via the innate immune response. They indicate that TXNRD1 and cGAS interaction is a relevant target for selectively suppressing inflammaging.

2022-06-14 | MSV000089650 | MassIVE

TXNRD1 drives innate immune response in senescent cells and promotes age-associated inflammation I

Project description:Sterile inflammation, also known as “inflammaging”, is a hallmark of tissue ageing. Cellular senescence contributes to tissue aging in part through secretion of proinflammatory factors known as senescence-associated secretory phenotype (SASP). Thioredoxin reductase 1 (TXNRD1) genetic variability is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living, and physical performance at old age. TXNRD1’s role in regulating tissue ageing has been attributed to its enzymatic role in reducing reactive oxygen species. Here we show that TXNRD1 drives SASP and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independent of its enzymatic activity

2023-05-25 | GSE202664 | GEO

TXNRD1 drives innate immune response in senescent cells and promotes age-associated inflammation II

2023-05-25 | GSE204841 | GEO

Loss of macrophage miR-146b with aging contributes to inflammation and mitochondrial dysfunction

Project description:Macrophages undergo programmatic changes with age leading to altered cytokine polarization and immune dysfunction, shifting these critical immune cells from protective sentinels to disease promoters. The molecular mechanisms underlying macrophage inflammaging are poorly understood. Using an unbiased RNA-seq approach, we identified miR-146b as the only microRNA whose expression progressively and unidirectionally declined with age in murine macrophages. miR-146b deficiency led to altered macrophage cytokine expression and reduced mitochondrial metabolic activity, two hallmarks of cellular aging. Single-cell RNA sequencing identified patterns of altered inflammation and interferon gamma signaling in miR-146b deficient macrophages. Identification of miR-146b as a potential regulator of macrophage aging provides novel insights into immune dysfunction associated with aging.

2021-08-24 | GSE164476 | GEO

Single-cell RNA-sequencing of CD45+ splenocytes from aged WT, miR146a knockout, and miR146a-miR155 T cell conditional double knockout mice

Project description:Chronic age-dependent inflammation, or inflammaging, is a risk-factor for many disorders that emerge in aging human populations. Mechanisms underlying these aberrant immune responses are complex and remain to be elucidated. Among recently appreciated regulators of inflammaging are microRNAs; one example of which is the anti-inflammatory miR-146a, where deficient mice succumb to life-shortening chronic inflammation. In this study, we found that deletion of miR-155 in T cells significantly extends the lifespan of miR-146a-/- mice. Using single-cell RNA sequencing and flow cytometry we found that miR-155 promotes the activation of effector T cell populations, including Tfh cells, in mice aged over 15 months. This correlated with miR-155 dependent increases in germinal center B cells, autoantibody responses and serum IgG targeting tissue antigens throughout the body. Mechanistically, we found that the aerobic glycolysis genes are elevated in T cells during aging, and to even greater levels in the absence of miR-146a, and this was reduced upon deleting miR-155 in T cells. Finally, through deletion of the mitochondrial pyruvate carrier (MPC) complex in T cells, which skews metabolism towards aerobic glycolysis, we demonstrate that several of the age-dependent, activation phenotypes of miR-146a-/- T cells were recapitulated, thus revealing the sufficiency of metabolic reprogramming to influence immune cell functions during aging. Altogether, these data indicate that miRNAs play pivotal roles in regulating lifespan through T cell mediated inflammaging.

2020-01-31 | GSE138222 | GEO

Expression data from skeletal muscles of flies with muscle-specific overexpression of Foxo or Mnt

Project description:Skeletal muscle senescence influences whole organism aging, yet little is known on the relay of pro-longevity signals from muscles to other tissues. We performed an RNAi screen in Drosophila for muscle-released cytokines ('myokines') regulating lifespan and identified Myoglianin, the homolog of human Myostatin. Myoglianin is induced in skeletal muscles by the transcription factor Mnt and together they constitute an inter-organ signaling module that regulates lifespan, age-related muscle dysfunction, and protein synthesis across aging tissues. Both Mnt and Myoglianin activate already in young age the protective decline in protein synthesis that is typical of old age, while knock-down of Myoglianin impairs this process. Mechanistically, Mnt decreases the expression of nucleolar components in muscles while also decreasing nucleolar size in distant tissues via Myostatin/p38 MAPK signaling. Our results highlight a myokine-dependent inter-organ longevity pathway that coordinates nucleolar function and protein synthesis across aging tissues. Affymetrix microarrays were used to evaluate genome-wide expression in skeletal muscles of flies with muscle-specific overexpression of FOXO or Mnt (Affymetrix Drosophila Genome 2.0 Array). This design allowed us to identify genes and pathways induced by overexpression of FOXO and/or Mnt, and enabled us to address the degree to which FOXO-induced pathways were independent of those induced by Mnt. Three independent biological replicates from each of three groups (control, UAS-Foxo and UAS-Mnt)

2014-07-02 | E-GEOD-39877 | biostudies-arrayexpress

Stat1 activation, through systemic interferon signaling, and upregulation of innate immune system receptors drives inflammaging, that is ameliorated by dietary restriction intervention [RNA-seq]

Project description:Aging is the result of an accumulation of molecular damages, driven by multiple factors like metabolic and oxidative stress, (epi)genetic alterations, and microbiome dysbiosis. In addition, aging is characterized by a chronic, low-grade inflammation known as inflammaging that represents a high significant risk factor for most, if not all, age-related diseases. Dietary restriction (DR) is the best-known non-invasive method to ameliorate the aging phenotype in many organisms. While it has been shown that DR reduces the inflammation in some tissues, the molecular mechanisms in old individuals are still largely unknown. Here we identify a multi-tissue gene network which regulates the inflammaging and that is ameliorated by DR. Using transcriptional profiling (RNA-seq), we found that aging upregulates the innate immune system receptor together with the activation of a systemic interferon (IFN) signaling through the Interferon Regulatory Factors (Irf), inflammatory cytokines and finally Stat1 transcription factor. Our results suggest that DR is able to ameliorate inflammaging by downregulating the expression and the activity of almost all the components of this gene network. In addition, chromatin accessibility genome-wide analysis showed that the binding site of Irf and Stat1 in the promoter of their target genes are more open in aging and become closer upon DR treatment indicating a transcriptional control of the inflammaging phenotype involving epigenetic modifications. Our results provide a comprehensive understanding of the molecular network regulating the inflammation in aging and DR and present novel anti-inflammaging therapeutic targets.

2022-08-25 | GSE162802 | GEO

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