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Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice [ATAC_invivo]

ABSTRACT: Low-grade chronic inflammation is considered a hallmark of ageing and associated with impaired tissue function and development of disease. However, how cell-intrinsic and -extrinsic factors interact to establish this phenotype, termed inflammaging, remains poorly understood. We addressed this question in the mouse intestinal epithelium, using organoid cultures to dissect stem cell-intrinsic and -extrinsic sources of increased inflammatory signaling upon ageing. At the single-cell level, we found that inflammaging establishes differently in cells along the crypt-villus axis, including intestinal stem cells (ISCs). Importantly, the inflammaging phenotype was stably propagated by aged ISCs in organoid cultures and associated with increased chromatin accessibility of inflammation-associated loci in vivo and ex vivo, indicating a cell-intrinsic memory of inflammation. Mechanistically, we show that expression of inflammaging genes is dependent on STAT1 signaling. Together, our data reveal that inflammaging in the intestine is promoted by a cell-intrinsic mechanism, stably propagated by ISCs and associated with a disbalance in immune homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE233898 | GEO | 2023/10/26

REPOSITORIES: GEO

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Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice [Capture-C]

Project description:Low-grade chronic inflammation is considered a hallmark of ageing and associated with impaired tissue function and development of disease. However, how cell-intrinsic and -extrinsic factors interact to establish this phenotype, termed inflammaging, remains poorly understood. We addressed this question in the mouse intestinal epithelium, using organoid cultures to dissect stem cell-intrinsic and -extrinsic sources of increased inflammatory signaling upon ageing. At the single-cell level, we found that inflammaging establishes differently in cells along the crypt-villus axis, including intestinal stem cells (ISCs). Importantly, the inflammaging phenotype was stably propagated by aged ISCs in organoid cultures and associated with increased chromatin accessibility of inflammation-associated loci in vivo and ex vivo, indicating a cell-intrinsic memory of inflammation. Mechanistically, we show that expression of inflammaging genes is dependent on STAT1 signaling. Together, our data reveal that inflammaging in the intestine is promoted by a cell-intrinsic mechanism, stably propagated by ISCs and associated with a disbalance in immune homeostasis.

2023-10-26 | GSE233899 | GEO

Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice [single-cell RNA-seq]

Project description:During ageing, cell-intrinsic and extrinsic factors lead to the decline of tissue function and organismal health. Disentangling these factors is important for developing effective strategies to prolong organismal healthspan. Here, we addressed this question in the mouse intestinal epithelium, which forms a dynamic interface with its microenvironment and receives extrinsic signals affecting its homeostasis and tissue ageing. We systematically compared transcriptional profiles of young and aged epithelial cells in vivo and ex vivo in cultured intestinal organoids. We found that all cell types of the aged epithelium exhibit an inflammation phenotype, which is marked by MHC class II upregulation and most pronounced in enterocytes. This was accompanied by elevated levels of the immune tolerance markers PD-1 and PD-L1 in the aged tissue microenvironment, indicating dysregulation of immunological homeostasis. Intestinal organoids from aged mice still showed an inflammation signature after weeks in culture, which was concurrent with increased chromatin accessibility of inflammation-associated loci. Our results reveal a cell-intrinsic, persistent inflammation phenotype in aged epithelial cells, which might contribute to systemic inflammation observed during ageing.

2023-10-26 | GSE190848 | GEO

Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice [ATAC-Seq]

2023-10-26 | GSE190285 | GEO

Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice [ex vivo bulk RNA-Seq]

2023-10-26 | GSE190282 | GEO

Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice [in vivo bulk RNA-Seq]

2023-10-26 | GSE190082 | GEO

Altered microRNA expression links IL6 and TNF-induced inflammaging with myeloid malignancy [miR146aKO_LSK_WGBS]

Project description:Aging is associated with significant changes in the hematopoietic system, including increased inflammation, impaired hematopoietic stem cell (HSC) function, and increased incidence of myeloid malignancy. Inflammation of aging (“inflammaging”) has been proposed as a driver of age-related changes in HSC function and myeloid malignancy, but mechanisms linking these phenomena remain poorly defined. Here, we identify loss of miR-146a as driving aging-associated inflammation in AML patients. miR-146a expression declined in old wild-type mice, and loss of miR-146a promoted premature HSC aging and inflammation in young miR-146a-null mice, preceding development of aging-associated myeloid malignancy. Using single-cell assays of HSC quiescence, stemness, differentiation potential, and epigenetic state to probe HSC function and population structure, we found that loss of miR-146a depleted a subpopulation of primitive, quiescent HSCs. DNA methylation and transcriptome profiling implicated NF-κB, IL6, and TNF as potential drivers of HSC dysfunction, activating an inflammatory signaling relay promoting IL6 and TNF secretion from mature miR-146a-/- myeloid and lymphoid cells. Reducing inflammation by targeting Il6 or Tnf was sufficient to restore single-cell measures of miR-146a-/- HSC function and subpopulation structure, and reduced the incidence of hematological malignancy in miR 146a-/- mice. miR-146a-/- HSCs exhibited enhanced sensitivity to IL6 stimulation, indicating that loss of miR-146a affects HSC function via both cell-extrinsic inflammatory signals and increased cell-intrinsic sensitivity to inflammation. Thus, loss of miR 146a regulates cell-extrinsic and -intrinsic mechanisms linking HSC inflammaging to the development of myeloid malignancy.

2020-05-14 | GSE148989 | GEO

Altered microRNA expression links IL6 and TNF-induced inflammaging with myeloid malignancy [miR146aKO_ESLAM_SCBS]

2020-05-14 | GSE148988 | GEO

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

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

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