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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE205206 | GEO | 2023/05/25

REPOSITORIES: GEO

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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 II

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 | GSE204841 | GEO

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

2023-05-25 | GSE202664 | GEO

L1 drives IFN in senescent cells and promotes age-associated inflammation.

Project description:Retrotransposable elements are deleterious at many levels, and the failure of host surveillance systems for these elements can thus have negative consequences. However, the contribution of retrotransposon activity to ageing and age-associated diseases is not known. Here we show that during cellular senescence, L1 (also known as LINE-1) retrotransposable elements become transcriptionally derepressed and activate a type-I interferon (IFN-I) response. The IFN-I response is a phenotype of late senescence and contributes to the maintenance of the senescence-associated secretory phenotype. The IFN-I response is triggered by cytoplasmic L1 cDNA, and is antagonized by inhibitors of the L1 reverse transcriptase. Treatment of aged mice with the nucleoside reverse transcriptase inhibitor lamivudine downregulated IFN-I activation and age-associated inflammation (inflammaging) in several tissues. We propose that the activation of retrotransposons is an important component of sterile inflammation that is a hallmark of ageing, and that L1 reverse transcriptase is a relevant target for the treatment of age-associated disorders.

| S-EPMC6519963 | biostudies-literature

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

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

| PRJNA844084 | ENA

Author Correction: L1 drives IFN in senescent cells and promotes age-associated inflammation.

Project description:An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

| S-EPMC7017651 | biostudies-literature

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

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

| PRJNA842434 | ENA

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

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

| PRJNA836900 | ENA

Neisseria gonorrhoeae-derived heptose elicits an innate immune response and drives HIV-1 expression.

Project description:Clinical and epidemiological synergy exists between the globally important sexually transmitted infections, gonorrhea and HIV. Neisseria gonorrhoeae, which causes gonorrhea, is particularly adept at driving HIV-1 expression, but the molecular determinants of this relationship remain undefined. N. gonorrhoeae liberates a soluble factor that potently induces expression from the HIV-1 LTR in coinfected cluster of differentiation 4-positive (CD4(+)) T lymphocytes, but this factor is not a previously described innate effector. A genome-wide mutagenesis approach was undertaken to reveal which component(s) of N. gonorrhoeae induce HIV-1 expression in CD4(+) T lymphocytes. A mutation in the ADP-heptose biosynthesis gene, hldA, rendered the bacteria unable to induce HIV-1 expression. The hldA mutant has a truncated lipooligosaccharide structure, contains lipid A in its outer membrane, and remains bioactive in a TLR4 reporter-based assay but did not induce HIV-1 expression. Mass spectrometry analysis of extensively fractionated N. gonorrhoeae-derived supernatants revealed that the LTR-inducing fraction contained a compound having a mass consistent with heptose-monophosphate (HMP). Heptose is a carbohydrate common in microbes but is absent from the mammalian glycome. Although ADP-heptose biosynthesis is common among Gram-negative bacteria, and heptose is a core component of most lipopolysaccharides, N. gonorrhoeae is peculiar in that it effectively liberates HMP during growth. This N. gonorrhoeae-derived HMP activates CD4(+) T cells to invoke an NF-?B-dependent transcriptional response that drives HIV-1 expression and viral production. Our study thereby shows that heptose is a microbial-specific product that is sensed as an innate immune agonist and unveils the molecular link between N. gonorrhoeae and HIV-1.

| S-EPMC3690901 | biostudies-other

JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer's disease.

Project description:Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer's disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death in AD progenitors and neurons. Notably, inhibiting c-Jun effectively blocks all these downstream molecular processes and rescues neuronal death and the impaired neurogenesis phenotype in AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.

| S-EPMC10696058 | biostudies-literature

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