Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Sep 20;10(9):e1338.
doi: 10.1002/cti2.1338. eCollection 2021.

Supranutritional selenium suppresses ROS-induced generation of RANKL-expressing osteoclastogenic CD4+ T cells and ameliorates rheumatoid arthritis

Jiahuan Qin  1 , Xia Huang  2 , Naiqi Wang  3 , Pengcheng Zhou  3 , Hao Zhang  4 , Zhian Chen  3 , Kaili Liang  1 , Dongcheng Gong  1 , Qunxiong Zeng  1 , Peng Niu  1 , Anping Chen  2 , Lin Yuan  5 , Zhaohui Yang  6 , Linchong Su  2 , Nan Shen  1   7 , Jun Deng  1   7 , Di Yu  1   3   4
Affiliations

Supranutritional selenium suppresses ROS-induced generation of RANKL-expressing osteoclastogenic CD4+ T cells and ameliorates rheumatoid arthritis

Jiahuan Qin et al. Clin Transl Immunology. .

Abstract

Objective: The benefit of Se supplementation in rheumatoid arthritis (RA) has been tested in clinical trials, but results remain inconclusive. The objective of this study was to specifically investigate the potential benefit of supranutritional Se by examining human samples from an area with supranutritional Se intake and testing a mouse model of RA.

Methods: Peripheral blood mononuclear cells (PBMCs) from RA patients (N = 57) and healthy controls (HC, N = 71) from an area of supranutritional Se intake (Enshi, Hubei, China) were analysed by flow cytometry. Serum cytokine and Se levels were measured by cytometric beads array (CBA) and inductively coupled plasma mass spectrometry (ICP-MS), respectively. With sufficient or supranutritional selenium intake, mice were induced with collagen-induced arthritis (CIA) and examined for disease activity and immunopathology. The influence of Se supplementation in the generation of RANKL-expressing osteoclastogenic CD4+ T cells was investigated by in vitro assays.

Results: In Enshi city, HC showed the above-normal concentrations of serum Se concentrations while RA patients were enriched in the normal range (70-150 ng mL-1) or below. RA patients with higher Se levels demonstrated milder disease and lower levels of C-reactive protein, IL-6, RANKL and Th17 cells. In the mouse CIA model, supranutritional Se supplementation delayed disease onset, ameliorated joint pathology and reduced CD4+CD44+RANKL+ T cells. Se supplementation could suppress RANKL expression in cultured mouse Th17 cells.

Conclusion: Supranutritional Se suppresses RANKL-expressing osteoclastogenic CD4+ T cells and could be beneficial to RA, which warrants formal testing in randomised clinical trials.

Keywords: RANKL; Th17 cells; rheumatoid arthritis; selenium.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Supranutritional serum Se levels negatively correlate with disease activity of patients with RA. (a–c) Comparison of serum Se level in patients with rheumatoid arthritis (RA, N = 57) and healthy controls (HC, N = 71) (a), female RA patients (N = 41) and HCs (N = 50) (b), male RA patients (N = 16) and HCs (N = 21) (c). (d) Comparison of RA frequencies among low (< 70 ng mL−1), normal (70‐150 ng mL−1) and high (> 150 ng mL−1) Se groups in pooled HC and RA. (e–g) Correlation between serum Se level and clinical parameters DAS28 (e), CRP (f), ESR (g) of RA patients. (h) Correlation between serum Se level and anti‐CCP and RF of RA patients. Data are shown as Median and analysed by the Mann–Whitney U‐test (a–c). Frequency comparison was calculated by a chi‐square test (d). The correlations were determined by using Spearman’s correlation coefficient (e–h). * P‐value < 0.05, ** P‐value < 0.01.
Figure 2
Figure 2
Supranutritional selenium levels correlate with declined serum IL‐6, RANKL and Th17 cells in patients with RA. (a) Representative FASC plots showing CD4 T‐cell subsets (Treg cells (CD4+CD127−CD25+), Th1 cells (CD4+CD45RA−CCR6−CXCR3+), Th2 cells (CD4+CD45RA−CCR6−CXCR3−) and Th17 cells (CD4+CD45RA−CCR6+CXCR3−)). (b) Correlation between serum Se levels and Treg/CD4 in RA patients. (c) Correlation between serum selenium level and the frequencies of Treg cells, Th1 cells, Th2 cells and Th17 cells in RA patients. (d–f) Comparison of IL‐6 and TNF‐α (D), IL‐2, IFN‐γ, IL‐4, IL‐17, IL‐21 and IL‐10 (e), RANKL levels (f) in HCs (N = 71) and RA patients (N = 57). (g, h) Correlation between serum Se levels and IL‐6, RANKL (g), IL‐17 in RA patients. (h) Correlation between serum Se levels and IL‐17 in RA patients. Data are shown as median and analysed by the Mann–Whitney U‐test (d–f). Correlations were determined by using Spearman’s correlation coefficient (b, c, g, h). * P‐value < 0.05, ** P‐value < 0.01.
Figure 3
Figure 3
Se supplementation ameliorates collagen‐induced arthritis in mice. (a) Serum selenium concentration in DBA (grey circle), DBA mice with CIA control (CIA, red circle) and selenium supplementation (CIA+Se, blue circle). (b–g) Kinetics of body weight changes (b), arthritis incidence (c), clinical score (d), hinder paw thickness (e) and histopathology (f), knee joints histopathology (f, g) in mice with CIA in control and +Se groups. Data are shown for individual (dots, n = 5) and mean (bars) values and analysed by the Kaplan–Meier curves by the log‐rank test (d), and the Mann–Whitney U‐test (a, e) unpaired t‐test. * P‐value < 0.05, ** P‐value < 0.01. Results are representative of three independent experiments.
Figure 4
Figure 4
The effect of Se supplementation on CD4+ T‐cell activation and effector differentiation in CIA mice. (a, b) Comparison of naïve T cells (CD4+CD44−CD62L+) and effector CD4+ T cells (Teff cells, CD4+CD44+CD62L−) (a) and Treg cells (CD4+Foxp3+) (b) in inguinal lymph nodes (LN) and spleens (SPL) of mice with CIA in control (red dots) and +Se groups (blue dots). (c, d) Representative FASC plots and statistics showing the frequencies of CD4+CD44+TNF‐α+ cells, CD4+CD44+IFN‐γ+ cells, CD4+CD44+IL‐17+ cells (c) and CD4+CD44+RANKL+ cells (d) in SPs and LNs of CIA (red dots) and CIA plus selenium (blue dots). Data are shown for individual (n = 7) and mean (bars) values and analysed by the Mann–Whitney U‐test. * P‐value < 0.05, ** P‐value < 0.01. Results are representative of three independent experiments.
Figure 5
Figure 5
Se supplementation differentially regulates IL‐17 and RANKL expression in polarised CD4+ T cells. (a) CFSE‐labelled proliferation assay of wild‐type naïve CD4+ T cells cultured under a Th17‐polariised condition plus Se‐Met for 72 h. (b) Representative FASC plots and statistics showing the percentages of apoptotic cells (Annexin V+PI+ plus Annexin V+PI−) of wild‐type naïve CD4+ T cells cultured under Th17‐induction conditions with or without Se‐Met for 72 h. (c, d) CFSE‐labelled proliferation assay of IL‐17 (c) and RANKL (d) ratios in each generation in WT naïve CD4+ T cells under Th17 cell‐induction conditions, with or without Se‐Met. Data are shown for individual (n = 4) and mean (bars) values and analysed by the Mann–Whitney U‐test (b) and the ANOVA test (a, c, d). * P‐value < 0.05, ** P‐value < 0.01. Results are representative of three independent experiments.
Figure 6
Figure 6
Se supplementation attenuates ROS to suppress RANKL expression in activated CD4+ T cells. (a, b) Representative FASC plots and statistics showing the frequencies of IL‐17 (a) and RANKL (b) and in WT and Tcf7‐KO with or without Se‐Met for 72 h. (c, d) RANKL (c) and IL‐17 (d) expression on CD4+ T cells increased with different doses of TCR stimulation. (e) The levels of ROS in cultured CD4+ T cells with or without Se‐Met. (f, g) Representative FASC plots and statistics showing the frequencies of RANKL (f) and IL‐17 (g) under Th17 cell‐induction conditions, with or without Se‐Met or NAC treatment. Data are shown for individual (n = 4) and mean (bars) values and analysed by the Mann–Whitney U‐test. * P‐value < 0.05, ** P‐value < 0.01. Results are representative of three independent experiments.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Rayman MP. Selenium and human health. Lancet 2012; 379: 1256–1268. - PubMed
    1. Zoidis E, Seremelis I, Kontopoulos N, Danezis GP. Selenium‐dependent antioxidant enzymes: actions and properties of selenoproteins. Antioxidants 2018; 7: 66. - PMC - PubMed
    1. Dixon S, Lemberg K, Lamprecht Met al. Ferroptosis: an iron‐dependent form of nonapoptotic cell death. Cell 2012; 149: 1060–1072. - PMC - PubMed
    1. Stockwell BR, Friedmann Angeli JP, Bayir Het al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017; 171: 273–285. - PMC - PubMed
    1. Ingold I, Berndt C, Schmitt Set al. Selenium utilization by GPX4 is required to prevent hydroperoxide‐induced ferroptosis. Cell 2018; 172(409–422): e421. - PubMed