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Senescent thymic stromal cells (TSCs) producing senescence-associated secretory phenotype (SASP) may play a role at later phases of thymic involution. However, the etiology and mechanisms responsible for TSC senescence remain to be elucidated. In the present study, the effects of oxidative stress on TSCs and role of miRNA-146a-5p in stress-induced premature senescence (SIPS) were identified. D-galactose (D-gal) induced oxidative stress in primary TSCs and a limited cumulative oxidative stress induced premature senescence but not apoptosis of TSCs. miRNA-146a-5p overexpression can mitigate the SIPS by targeting tumor necrosis factor receptor-associated factor 6 (TRAF6) instead of increasing autophagy clearance. Furthermore, exogenous miRNA-146a-5p reversed the upregulation of chemokines including Cxcl5, pro-inflammatory cytokines, and antimicrobial peptides in TSCs with SIPS. In conclusion, the accumulated oxidative stress may be partially responsible for senescence in TSCs and modulation of miRNA-146a-5p may attenuate this process., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Adipocyte accumulation is a predominant feature of age-related thymic involution, but the mechanisms responsible for thymic adipogenesis remain to be elucidated. The aim of this study was to identify key regulators in thymic adipogenesis. We used rosiglitazone, a potent peroxisome proliferator-activated receptor γ (PPARγ) agonist, to induce adipogenic differentiation of OP9-DL1 cells, and investigated the differentially expressed proteins during adipogenic differentiation by using label-free quantitative proteomics. Furthermore, the effects of transforming growth factor β1 (TGF-β1) on rosiglitazone-induced adipogenic differentiation of OP9-DL1 cells as well as the underlying mechanisms were also investigated. Results: Proteomic analysis identified 139 proteins differed significantly in rosiglitazone-treated cells compared with dimethyl sulphoxide (DMSO)-treated cells. Rosiglitazone-induced adipogenic differentiation was inhibited by TGF-β1 treatment in OP9-DL1 cells and primary thymic stromal cells. Real-time PCR analysis showed significant increases in PPARγ and fatty acid binding protein 4 mRNA levels in rosiglitazone-treated cells, which were inhibited by TGF-β1 treatment. TGF-β1 down-regulated PPARγ expression at both mRNA and protein levels in OP9-DL1 cells. Chromatin immunoprecipitation analysis demonstrated that TGF-β1 enhanced the binding of Smad2/3 and histone deacetylase 1, but reduced the binding of H3K14ac to the promoter of PPARγ gene. TGF-β1 partially reversed the inhibitory effects of rosiglitazone on the expression of Axin2 and β-catenin protein levels. TGF-β1 inhibited rosiglitazone-induced adipogenic transformation in OP9-DL1 cells by down-regulation of PPARγ and activation of the canonical Wnt/β-catenin signaling pathway. Conclusion: Taken together, activation of TGF-β pathway may serve as a useful strategy to prevent thymic adiposity in age-related thymic involution. [ABSTRACT FROM AUTHOR]