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Vitamin D₃ inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing.

ABSTRACT: Vitamin D₃ replacement in older insufficient adults significantly improves their antigen-specific varicella zoster virus (VZV) cutaneous immunity. However, the mechanisms involved in this enhancement of cutaneous immunity are not known. Here, we show for the first time that vitamin D₃ blocks the senescence-associated secretory phenotype (SASP) production by senescent fibroblasts by partially inhibiting the p38 MAPK pathway. Furthermore, transcriptomic analysis of skin biopsies from older subjects after vitamin D₃ supplementation shows that vitamin D₃ inhibits the same inflammatory pathways in response to saline as the specific p38 inhibitor, losmapimod, which also enhances immunity in the skin of older subjects. Vitamin D₃ supplementation therefore may enhance immunity during ageing in part by blocking p38 MAPK signalling and in turn inhibit SASP production from senescent cells in vivo.

SUBMITTER: Sayegh S

PROVIDER: S-EPMC11019144 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Vitamin D3 inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing.

Sayegh Souraya S Fantecelle Carlos Henrique CH Laphanuwat Phatthamon P Subramanian Priya P Rustin Malcom H A MHA Gomes Daniel C O DCO Akbar Arne N AN Chambers Emma S ES

Aging cell 20240129 4

Vitamin D3 replacement in older insufficient adults significantly improves their antigen-specific varicella zoster virus (VZV) cutaneous immunity. However, the mechanisms involved in this enhancement of cutaneous immunity are not known. Here, we show for the first time that vitamin D3 blocks the senescence-associated secretory phenotype (SASP) production by senescent fibroblasts by partially inhibiting the p38 MAPK pathway. Furthermore, transcriptomic analysis of skin biops ...[more]

PMID: 38287646

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Project description:Ataxia-telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of the homeostatic protein kinase ATM. The complex phenotype of A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts from A-T patients exhibit premature senescence, highlighting the association between genome instability, cellular senescence, and aging. We found that lung fibroblasts derived from ATM-deficient mice provide a versatile experimental system to explore the mechanisms driving the premature senescence of primary fibroblasts lacking ATM. Atm-/- fibroblasts failed to proliferate under ambient oxygen conditions (21%). Although they initially proliferated under physiological oxygen levels (3%), they rapidly entered senescence. In contrast, wild-type (WT) lung fibroblasts did not senesce under 3% oxygen and eventually underwent immortalization and neoplastic transformation. However, rapid senescence could be induced in WT cells either by Atm gene ablation or persistent chemical inhibition of ATM kinase activity, with senescence induced by ATM inhibition being reversible upon inhibitor removal. Moreover, the concomitant loss of ATM and p53 led to senescence evasion, vigorous growth, rampant genome instability, and subsequent immortalization and transformation. Our findings reveal that the rapid senescence of Atm-/- lung fibroblasts is driven by the collaborative action of the cGAS-STING, p38 MAPK, and p53 pathways in response to persistent DNA damage, ultimately leading to the induction of interferon-α1 and downstream interferon-stimulated genes. We propose that accelerated cellular senescence may exacerbate specific A-T symptoms, particularly contributing to the progressive, life-threatening interstitial lung disease often observed in A-T patients during adulthood.

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Vitamin D₃ inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing.

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Vitamin D<sub>3</sub> inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing.

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Vitamin D3 inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing.

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Vitamin D&lt;sub&gt;3&lt;/sub&gt; inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing.

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OmicsDI is part of the ELIXIR infrastructure

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Vitamin D₃ inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing.

Vitamin D<sub>3</sub> inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing.