Dataset Information

Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1.

ABSTRACT: Vitamin D has multiple roles, including the regulation of bone and calcium homeostasis. Deficiency of 25-hydroxyvitamin D, the major circulating form of vitamin D, is associated with an increased risk of age-related chronic diseases, including Alzheimer's disease, Parkinson's disease, cognitive impairment, and cancer. In this study, we utilized Caenorhabditis elegans to examine the mechanism by which vitamin D influences aging. We found that vitamin-D3-induced lifespan extension requires the stress response pathway genes skn-1, ire-1, and xbp-1. Vitamin D3 (D3) induced expression of SKN-1 target genes but not canonical targets of XBP-1. D3 suppressed an important molecular pathology of aging, that of widespread protein insolubility, and prevented toxicity caused by human ?-amyloid. Our observation that D3 improves protein homeostasis and slows aging highlights the importance of maintaining appropriate vitamin D serum levels and may explain why such a wide variety of human age-related diseases are associated with vitamin D deficiency.

SUBMITTER: Mark KA

PROVIDER: S-EPMC5689451 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1.

Mark Karla A KA Dumas Kathleen J KJ Bhaumik Dipa D Schilling Birgit B Davis Sonnet S Oron Tal Ronnen TR Sorensen Dylan J DJ Lucanic Mark M Brem Rachel B RB Melov Simon S Ramanathan Arvind A Gibson Bradford W BW Lithgow Gordon J GJ

Cell reports 20161001 5

Vitamin D has multiple roles, including the regulation of bone and calcium homeostasis. Deficiency of 25-hydroxyvitamin D, the major circulating form of vitamin D, is associated with an increased risk of age-related chronic diseases, including Alzheimer's disease, Parkinson's disease, cognitive impairment, and cancer. In this study, we utilized Caenorhabditis elegans to examine the mechanism by which vitamin D influences aging. We found that vitamin-D3-induced lifespan extension requires the str ...[more]

PMID: 27783938

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Project description:Background:Both endoplasmic reticulum (ER) stress and macrophage diversity contribute to inflammatory processes in lung injury. However, the interaction between ER stress and macrophage M1/M2 imbalance in lung inflammation remains unclear. The present study, thus, aimed to evaluate the role of ER stress-mediated macrophage phenotype changes in lipopolysaccharide (LPS)-induced acute lung injury (ALI). Methods:Lung inflammation and injury were examined in a murine model of LPS-induced ALI with or without ER stress inhibitors. Alveolar macrophage (AM) polarization was determined by flow cytometry. Bone marrow-derived macrophages (BMDMs) were treated with either an ER stress inducer, inhibitor, or an IRE-1 endonuclease inhibitor before being polarized to an M1 and M2 phenotype. The macrophage polarization status was examined via RT-PCR and flow cytometry. Results:Our results indicated that ER stress and IRE-1/XBP-1 signaling are activated in LPS-induced ALI. Furthermore, we observed that AM polarizes to an inflammatory phenotype upon exposure to LPS in the induction phase and an anti-inflammatory phenotype in the resolution phase of lung inflammation. Inhibition of ER stress attenuated the pathophysiological features of LPS-induced lung inflammation/injury, as evidenced by a decrease in bronchoalveolar lavage (BAL) protein levels, the number of inflammatory cells, and the expression level of inflammatory mediators. In addition, the ER stress inducer promoted M1 polarization and the switch from M2 to M1 in BMDMs, whereas inhibition of ER stress and XBP-1 splicing suppressed M1 but did not promote M2, both in vivo and in vitro. Conclusions:Our results demonstrated that inhibition of the ER stress-associated IRE-1/XBP-1 signaling pathway suppresses M1 polarization and ameliorates LPS-induced lung injury. This indicates that the interaction between ER stress and macrophage polarization might be a novel therapeutic target for endotoxin-induced lung inflammatory disorders.

Dataset Information

Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1.

Publications

Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1.

Similar Datasets

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