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• Research Paper Volume 12, Issue 12 pp 12032-12050

  CD70 contributes to age-associated T cell defects and overwhelming inflammatory responses

  Relevance score: 9.611616

  Di Wang, Juan Du, Yangzi Song, Beibei Wang, Rui Song, Yu Hao, Yongqin Zeng, Jiang Xiao, Hong Zheng, Hui Zeng, Hongxin Zhao, Yaxian Kong

  Keywords: CD70, T cell aging, immunosenescence, overwhelming inflammatory responses, co-inhibitory molecules

  Published in Aging on June 19, 2020

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  Aging is associated with immune dysregulation, especially T cell disorders, which result in increased susceptibility to various diseases. Previous studies have shown that loss of co-stimulatory receptors or accumulation of co-inhibitory molecules play important roles in T cell aging. In the present study, CD70, which was generally regarded as a costimulatory molecule, was found to be upregulated on CD4⁺ and CD8⁺ T cells of elderly individuals. Aged CD70⁺ T cells displayed a phenotype of over-activation, and expressed enhanced levels of numerous inhibitory receptors including PD-1, 2B4 and LAG-3. CD70⁺ T cells from elderly individuals exhibited increased susceptibility to apoptosis and high levels of inflammatory cytokines. Importantly, the functional dysregulation of CD70⁺ T cells associated with aging was reversed by blocking CD70. Collectively, this study demonstrated CD70 as a prominent regulator involved in immunosenescence, which led to defects and overwhelming inflammatory responses of T cells during aging. These findings provide a strong rationale for targeting CD70 to prevent dysregulation related to immunosenescence.

  

  CD70-expressing T cells accumulate with age. Flow cytometry analysis of CD70 expression on PBMCs from healthy controls of different ages. (A) Representative flow cytometric plots show the expression of CD70 gated on CD4⁺ and CD8⁺ T cells from five healthy donors in different age groups. (B–C) Box plots of the frequencies of CD70⁺ cells among CD4⁺ and CD8⁺ T cells from healthy donors in different age groups (n = 34-56 in each group). Values given are the median frequencies ± the interquartile range and 10 and 90 percentile whiskers. The p-values were obtained by Kruskal-Wallis test followed by Dunn’s multiple comparisons test. (D–E) Correlation analysis of age and surface CD70 expression on CD4⁺ T cells (D) and CD8⁺ T cells (E) from all healthy individuals. Spearman’s non-parametric test was used to test for correlations. *p < 0.05, **p < 0.01, ***p < 0.001.

  
  
  

  

  CD70 is preferentially expressed on memory CD4⁺ and CD8⁺ T cells. Expression of CD70 on each subset (T_N, T_CM, T_EM, and T_EMRA) of CD4⁺ and CD8⁺ T cells. Representative flow data (A, C) and box plots (B, D) of the percentage of CD70 expression on each subset of CD4⁺ (A–B) and CD8⁺ (C–D) T cells from five different age groups (n = 34-56 in each group). Data are shown as the median ± 95% confidence interval (CI). The p-values were obtained by Kruskal-Wallis test followed by Dunn’s multiple comparisons test. *p < 0.05, **p < 0.01, ***p < 0.001.

  
  
  

  

  Aged CD70⁺ T cells show a phenotype of over activation. Flow cytometry analysis of percentage of HLA-DR⁺ CD38^hi cells (A–B), and expression of CD28 (C–D) and CD27 (E–F) on CD70^- vs. CD70⁺ CD4⁺ and CD8⁺ T cells from elderly individuals (61-80 years, n = 17). Representative flow data or histograms (left) and plots (right) display the expression of the above receptors on CD70^- vs. CD70⁺ cells (gated with CD4⁺ or CD8⁺ T cells). The p-values were obtained by paired t-test (HLA-DR⁺CD38^hi [CD4⁺ T cells], CD28, CD27) or Wilcoxon matched-pairs signed rank test (HLA-DR⁺CD38^hi [CD8⁺ T cells]). ***p < 0.001.

  
  
  

  

  CD70 expression is associated with the phenotypic profile of exhaustion. Flow cytometry analysis of expression of PD-1 (A–B), 2B4 (C–D), LAG-3 (E–F) and CD160 (G–H) on CD70^- vs. CD70⁺ CD4⁺ and CD8⁺ T cells from elderly individuals (61-80 years, n = 17 [2B4, CD160], n = 34 [PD-1, LAG-3]). Representative histograms (left) and plots (right) display the expression of the above receptors on CD70^- vs. CD70⁺ cells (gated with CD4⁺ or CD8⁺ T cells). The p-values were obtained by paired t-test (PD-1 [CD4⁺ T cells], 2B4, CD160 [CD8⁺ T cells]) or Wilcoxon matched-pairs signed rank test (PD-1 [CD8⁺ T cells], LAG-3, CD160 [CD4⁺ T cells]). ***p < 0.001.

  
  
  

  

  Aged CD70⁺ T cells exhibit high susceptibility to apoptosis that can be reversed by blocking CD70. (A–D) Percentage of apoptotic cells (Annexin V⁺ 7AAD^-) (A–B) and expression of CD95 (C–D) in CD70^- and CD70⁺ T cells from elderly individuals (61-80 years, n = 17). Representative histograms (left) and plots (right) of the percentage of apoptotic cells are shown. The p-values were obtained by paired t-test (Annexin V) or Wilcoxon matched-pairs signed rank test (CD95). (E–F) Correlation analysis of percentage of HLA-DR⁺CD38^hi cells and percentage of Annexin V⁺ 7AAD^- cells (E) or CD95 expression (F) on CD4⁺ T cells (left) and CD8⁺ T cells (right) from all healthy donors. Spearman’s non-parametric test was used for correlation analysis. (G–J) Purified CD4⁺ and CD8⁺ T cells from elderly individuals (n = 8) were cultured in vitro with anti-human CD70 antibody or isotype IgG at a concentration of 10 μg/mL. After culturing for 24 h, the susceptibility to apoptosis was evaluated by flow cytometry. Representative histogram (left) and plot (right) of percentage of Annexin V⁺ 7AAD^- (G–H) and Annexin V⁺ CD95⁺ cells (I–J) in CD4⁺ and CD8⁺ T cells. The p-values were obtained by paired t-test (Annexin V⁺ 7AAD^- [CD8⁺ T cells], Annexin V⁺ CD95⁺ [CD8⁺ T cells]) or Wilcoxon matched-pairs signed rank test (Annexin V⁺ 7AAD^- [CD4⁺ T cells], Annexin V⁺ CD95⁺ [CD4⁺ T cells]). *p < 0.05, **p < 0.01, ***p < 0.001.

  
  
  

  

  Aged CD70⁺ T cells secrete increased levels of inflammatory cytokines that can be reversed by blocking CD70. (A–F) Intracellular staining for TNF-α, IFN-γ, and IL-2 in CD70^- and CD70⁺ T cells from elderly individuals (61-80 years, n = 17) after in vitro anti-CD3/anti-CD28 stimulation. Representative flow data (left) and plots (right) for TNF-α, IFN-γ, and IL-2, respectively. The p-values were obtained by paired t-test (TNF-α, IFN-γ [CD8⁺ T cells], IL-2 [CD4⁺ T cells]) or Wilcoxon matched-pairs signed rank test (IFN-γ [CD4⁺ T cells], IL-2 [CD8⁺ T cells]). (G–L) Purified CD4⁺ and CD8⁺ T cells from healthy individuals (n = 6) were cultured with antagonist anti-CD70 antibody or IgG at a concentration of 10 μg/mL as indicated. After culturing in vitro for 24 h and stimulating with anti-CD3/anti-CD28, the cytokine production was measured by flow cytometry. Representative histogram (left) and plot (right) of TNF-α, IFN-γ, and IL-2 expression in CD4⁺ and CD8⁺ T cells. The p-values were obtained by paired t-test. *p < 0.05, **p < 0.01, ***p < 0.001.

  
  
  

• Research Paper Volume 12, Issue 2 pp 1141-1158

  MiR-29b-3p promotes particulate matter-induced inflammatory responses by regulating the C1QTNF6/AMPK pathway

  Relevance score: 7.734088

  Jian Wang, Mengchan Zhu, Ling Ye, Cuicui Chen, Jun She, Yuanlin Song

  Keywords: particulate matter, miR-29b-3p, complement C1q tumor necrosis factor-related protein 6, AMPK pathway, inflammatory responses

  Published in Aging on January 18, 2020

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  Inflammatory responses are considered to be the critical mechanism underlying particulate matter (PM)-induced development and exacerbation of chronic respiratory diseases. MiR-29b-3p has been found to participate in various biological processes, but its role in PM-induced inflammatory responses was previously unknown. Here, we constructed a miRNA PCR array to find that miR-29b-3p was the most highly expressed in human bronchial epithelial cells (HBECs) exposed to PM. MiR-29b-3p promoted PM-induced pro-inflammatory cytokines (IL-1β, IL-6, and IL-8) expression via inhibiting the AMPK signaling pathway in HBECs. RNA sequencing and luciferase reporter assay identified that miR-29b-3p targeted complement C1q tumor necrosis factor-related protein 6 (C1QTNF6), a protein that protected from PM-induced inflammatory responses via activating the AMPK signaling pathway. In vivo, miR-29b-3p antagomirs delivered via the tail vein prior to PM exposure significantly counteracted PM-induced miR-29b-3p upregulation and C1QTNF6 downregulation in lung tissues. Furthermore, miR-29b-3p inhibition alleviated inflammatory cells infiltration and pro-inflammatory cytokines secretion in the lung of PM-exposed mice. These findings firstly revealed that miR-29b-3p acted as a novel modulator of PM-induced inflammatory responses by targeting the C1QTNF6/AMPK signaling pathway, which contributes to a better understanding of the biological mechanisms underlying adverse PM-induced respiratory health effects.

  

  MiR-29b-3p was upregulated upon PM exposure. (A) The expression of miRNAs was measured using a inflammation-related miRNAs PCR array in HBECs with or without 300 μg/cm³ PM for 24 h. The points outside the dashed lines indicated miRNAs with fold change > 2 among the subsets (n= 2 biological replicates). (B) Real-time PCR analysis of miR-29b-3p expression in HBECs, MLE-12, and RAW264.7 cells with or without 300 μg/cm³ PM for 24 h. (C) HBECs were stimulated with different doses of PM (50, 100, 200, and 300 μg/cm³) for 24 h and the expression of miR-29b-3p was detected using real-time PCR. (D) HBECs were treated with 300 μg/cm³ PM for different durations (3, 6, 12, and 24 h) and the expression of miR-29b-3p was detected using real-time PCR. Values represent mean ± SEM; *, P<0.05, compared with the control group; n=3. HBECs, human bronchial epithelial cells; PM, particulate matter.

  
  
  

  

  MiR-29b-3p promoted PM-induced inflammatory responses via repressing AMPK pathway activation. (A) HBECs were transfected with miR-29b-3p mimic (29b-m) or negative control mimic (NC-m), and then treated with or without 300 μg/cm³ PM for 24 h. Real-time PCR analysis of IL-1β, IL-6, and IL-8 expression in HBECs transfected with 29b-m or NC-m prior to PM exposure. Values represent mean ± SEM; *, P<0.05, compared with the NC-m + PM group; #, P<0.05, compared with the NC-m group; n=3. (B) HBECs were transfected with miR-29b-3p inhibitor (29b-i), or negative control inhibitor (NC-i), and then treated with or without 300 μg/cm³ PM for 24 h. Real-time PCR analysis of IL-1β, IL-6, and IL-8 expression in HBECs transfected with 29b-i or NC-i prior to PM exposure. Values represent mean ± SEM; *, P<0.05, compared with the NC-i + PM group; #, P<0.05, compared with the NC-i group; n=3. (C) Western blot analysis of AMPK signaling pathway activation in HBECs transfected with 29b-m or NC-m prior to PM exposure. The optical densities of protein bands were shown in (D). Values represent mean ± SEM; *, P<0.05, compared with the NC-m + PM group; n=3. (E) The AMPK siRNAs were transfected into HBECs 24h prior to PM exposure, respectively and the optimum AMPK siRNA was selected using real-time PCR. Values represent mean ± SEM; *, P<0.05, compared with the NC siRNA group; n=3. (F) Real-time PCR analysis of IL-1β, IL-6, and IL-8 expression in HBECs transfected with AMPK siRNA or negative control siRNA prior to PM exposure. Values represent mean ± SEM; *, P<0.05, compared with the NC siRNA + PM group; #, P<0.05, compared with the NC siRNA group; n=3. HBECs, human bronchial epithelial cells; PM, particulate matter.

  
  
  

  

  C1QTNF6 is the target gene of miR-29b-3p. (A) HBECs were transfected with miR-29b-3p mimic (29b-m) or negative control mimic (NC-m), respectively, and then treated with or without 300 μg/cm³ PM for 24 h. RNA sequencing identified the differentially-expressed genes in HBECs in the four groups (NC-m, 29b-m, NC-m + PM, and 29b-m + PM). The heatmap identified eight differentially downregulated genes common to the NC-m vs. 29b-m groups, NC-m + PM vs. 29b-m + PM groups, and NC-m vs. NC-m + PM groups. (B) Venn diagram showed the common differentially-downregulated genes in RNA sequencing and TargetScan analysis. (C) The binding sites between miR-29b-3p and the 3'UTR of C1QTNF6 were predicted by TargetScan. The aligned sequences of the 3'UTR of C1QTNF6 complementary to the seed sequence of miR-29b-3p and mutant sequences were shown. (D) HBECs were transfected with C1QTNF6-3'-UTR-WT, C1QTNF6-3'-UTR-mutA, C1QTNF6-3'-UTR-mutB or C1QTNF6-3'-UTR-mutAB plasmids combined with 29b-m or NC-m, respectively. The normalized luciferase activities were determined by luciferase reporter assay. Values represent mean ± SEM; *, P<0.05, compared with the WT plasmid + 29b-m group; n=6. (E) Real-time PCR analysis of C1QTNF6 expression in HBECs transfected with 29b-m or NC-m prior to PM exposure. Values represent mean ± SEM; *, P<0.05, compared with the NC-m + PM group; #, P<0.05, compared with the NC-m group; n=3. (F) Western blot analysis of C1QTNF6 expression in HBECs transfected with 29b-m, NC-m, miR-29b-3p inhibitor (29b-i), or negative control inhibitor (NC-i), respectively. (G) HBECs were stimulated with different doses of PM (50, 100, 200, and 300 μg/cm³) for 24 h and the mRNA expression of C1QTNF6 was detected using real-time PCR. (H) The protein expression of C1QTNF6 was detected using western blot analysis. The optical densities of protein bands were shown in (I). Values represent mean ± SEM; *, P<0.05, compared with the control group; n=3. HBECs, human bronchial epithelial cells; PM, particulate matter.

  
  
  

  

  C1QTNF6 overexpression attenuated PM-induced inflammatory responses. HBECs were transfected with C1QTNF6-overexpressing virus or negative control virus (EV). The C1QTNF6 overexpression efficiency was confirmed using real-time PCR (A) and western blot analysis (B). The optical densities of protein bands were shown in (C). Values represent mean ± SEM; *, P<0.05, compared with the EV group; n=3. (D) Real-time PCR analysis of IL-1β, IL-6, and IL-8 expression in C1QTNF6-overexpressing or negative control HBECs treated with or without 300 μg/cm³ PM for 24 h. (E) Western blot analysis of AMPK signaling pathway activation in C1QTNF6-overexpressed or negative control HBECs treated with or without 300 μg/cm³ PM for 24 h. The optical densities of protein bands were shown in (F). Values represent mean ± SEM; *, P<0.05, compared with the EV + PM group; #, P<0.05, compared with the EV group; n=3. EV, empty vector; HBECs, human bronchial epithelial cells; PM, particulate matter.

  
  
  

  

  C1QTNF6 silence enhanced the PM-induced inflammatory responses. HBECs were transfected with C1QTNF6 siRNA or negative control siRNA, respectively and then treated with or without 300 μg/cm³ PM for 24 h. (A) Real-time PCR analysis of C1QTNF6 expression in HBECs transfected with C1QTNF6 siRNA or negative control siRNA prior to PM exposure. (B) Real-time PCR analysis of IL-1β, IL-6, and IL-8 expression in HBECs transfected with C1QTNF6 siRNA or negative control siRNA prior to PM exposure. (C) Western blot analysis of the AMPK signaling pathway activation in HBECs transfected with C1QTNF6 siRNA or negative control siRNA prior to PM exposure. The optical densities of protein bands were shown in (D). Values present as mean ± SEM; *, P<0.05, compared with the NC siRNA + PM group; #, P<0.05, compared with the NC siRNA group; n=3. HBECs, human bronchial epithelial cells; PM, particulate matter.

  
  
  

  

  MiR-29b-3p inhibition attenuated the PM-induced acute lung inflammatory responses in vivo. The acute PM-exposed mouse model was constructed and miR-29b-3p antagomirs (29b-antago) or negative control antagomirs (NC-antago) were delivered via the tail vein of mice 24 h prior to the first PM exposure. (A) The histopathologic analysis of acute inflammatory responses in lung tissue of mice using H&E staining. (B) The numbers of total cells, macrophages and neutrophils in the BALF of mice were counted. (C) The concentrations of IL-1β, IL-6, and IL-8 in the BALF of mice were measured by ELISA. Values represent mean ± SEM; *, P<0.05, compared with the NC-antago + PM group; #, P<0.05, compared with the NC-antago group; n=3. BALF, bronchoalveolar lavage fluid; PM, particulate matter.

  
  
  

  

  MiR-29b-3p inhibited the expression of C1QTNF6 in vivo. The acute PM-exposed mouse model was constructed and miR-29b-3p antagomirs (29b-antago) or negative control antagomirs (NC-antago) were delivered through the tail vein of mice 24 h prior to the first PM exposure. (A) Real-time PCR analysis of C1QTNF6 expression in mouse models treated with 29b-antago or NC-antago. (B) Western blot analysis of C1QTNF6 expression in mouse models treated with 29b-antago or NC-antago. The optical densities of protein bands were shown in (C). Values represent mean ± SEM; *, P<0.05, compared with the NC-antago + PM group; #, &, P<0.05, compared with the NC-antago group; n=3-5. (D) Immunohistological analysis of C1QTNF6 expression in lung tissue of mouse models treated with 29b-antago or NC-antago. (E) Schematic diagram of the critical role of miR-29b-3p in the PM-induced inflammatory responses. miR-29b-3p was upregulated by PM exposure and inhibited the activation of AMPK pathway via targeting C1QTNF6 to promote PM-induced inflammatory responses. PM, particulate matter.

  
  
  

• Research Paper Volume 11, Issue 15 pp 5570-5578

  Effects of inflammatory responses, apoptosis, and STAT3/NF-κB- and Nrf2-mediated oxidative stress on benign prostatic hyperplasia induced by a high-fat diet

  Relevance score: 9.611616

  Yongzhi Li, Benkang Shi, Fengming Dong, Xingwang Zhu, Bing Liu, Yili Liu

  Keywords: benign prostatic hyperplasia, high-fat diet, inflammatory responses, apoptosis, oxidative stress

  Published in Aging on August 14, 2019

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  This study determined whether or not benign prostatic hyperplasia (BPH) induced by a high-fat diet (HFD) is involved in inflammatory responses, apoptosis, and the signal transducer and activator of transcription (STAT3)/nuclear factor-kappa B (NF-κB)- and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress pathways. Forty rats were divided into four groups: control; HFD; testosterone; and HFD+testosterone. Hematoxylin and eosin (HE) staining was used to assess histologic changes. An enzyme-linked immunosorbent assay and Western blot analysis were used to detect levels of related proteins. Compared with the control group, the prostate levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), transforming growth factor-β1 (TGF-β1), and monocyte chemotactic protein-1 (MCP-1) were significantly increased, while the levels of glutathione peroxidase (GSH-Px), glutathione reductase (GR), glutathione (GSH), and superoxide dismutase (SOD) were decreased. The TNF-κB, Bcl-2, and caspase-3 levels were increased, while the Bax level was markedly decreased. The cytoplasmic expression of STAT3 and NF-κB was increased, while the nuclear expression of Nrf2 was markedly decreased compared with the control group. In summary, our results demonstrated that a long-term HFD might cause changes in inflammatory responses, apoptosis, and oxidative stress, thus contributing to prostatic hyperplasia. The underlying mechanisms might be related to the STAT3/NF-κB- and Nrf2-mediated oxidative stress pathway.

  

  Histologic changes in rat prostate (HE stain, ×40). (A) Control group; (B) HFD group; (C) Testosterone group; (D) HFD+testosterone group.

  
  
  

  

  Effects of a long-term HFD on prostatic COX-2, iNOS, TNF-α, IL-6, TGF-β1, MCP-1, MDA, SOD, GSH-Px, GR, and GSH (A–K) levels by ELISA. Results are representative of three independent experiments. ^##p<0.01 and ^#p<0.05, compared with the control group; *p<0.05 compared with the testosterone group.

  
  
  

  

  Effects of a long-term HFD on the expression of NF-κB, Bcl-2, Bax, caspase-3, STAT3, NF-κB, p65, and Nrf2 protein.^##p<0.01 and ^#p<0.05 compared with the control group; *p<0.05 compared with the testosterone group.