Abstract
Neuroinflammation leads to tissue injury causing many of the clinical symptoms of Multiple Sclerosis, an autoimmune disorder of the central nervous system (CNS). While T cells, specifically Th1 and Th17 cells, are the ultimate effectors of this disease, dendritic cells (DCs) mediate T cell polarization, activation, etc. In our previous study, Apigenin, a natural flavonoid, has been shown to reduce EAE disease severity through amelioration of demyelination in the CNS as well as the sequestering of DCs and other myeloid cells in the periphery. Here, we show that Apigenin exerts its effects possibly through shifting DC modulated T cell responses from Th1 and Th17 type towards Treg directed responses evident through the decrease in T-bet, IFN-γ (Th1), IL-17 (Th17) and increase in IL-10, TGF-β and FoxP3 (Treg) expression in cells from both normal human donors and EAE mice. RelB, an NF-κβ pathway protein is central to DC maturation, its antigen presentation capabilities and DC-mediated T cell activation. Apigenin reduced mRNA and protein levels of RelB and also reduced its nuclear translocation. Additionally, siRNA-mediated silencing of RelB further potentiated the RelB-mediated effects of Apigenin thus confirming its role in Apigenin directed regulation of DC biology. These results provide key information about the molecular events controlled by Apigenin in its regulation of DC activity marking its potential as a therapy for neuroinflammatory disease.
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Abbreviations
- BBB:
-
Blood-brain barrier
- TNF-α:
-
Tumor necrosis factor
- IFN-γ:
-
Interferon-γ
- NF-κB:
-
Nuclear factor kappa B
- MS:
-
Multiple Sclerosis
- CNS:
-
Central nervous system
- EAE:
-
Experimental autoimmune encephalomyelitis
- Treg :
-
T regulatory cell
- DC:
-
Dendritic cells
- PBMC:
-
Peripheral blood mononuclear cell
- PBL:
-
Peripheral blood lymphocyte
- LPS:
-
Lipopolysaccharide
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These studies have been funded in part with NIH/NINDS R01 NS097147 to PJ. Authors also wish to acknowledge the National MS Society grant RG 4471A6/2 that supported FB.
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Conception and design (RG, PJ). In vitro DC and T cell assay design and execution (RG, RB, PM). Analysis and interpretation of data (RG). EAE in vivo mouse work (FB) while NS and MN kindly provided with splenocytes from naïve mice. 15-color flow cytometry data acquisition (MB). Drafting the manuscript (RG, PJ). Document revision and editing (RG, RB, PJ, ZKK). Final approval of the version to be published (ZKK, PJ). All authors have read and approved the final manuscript.
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Supplementary Figure 1
Antigen independent naïve T cell polarization. Splenocytes were pooled from naïve mice and total T cells were isolated as per the EasySep mouse T cell isolation protocol. T cells were stimulated for 72 h with different mixtures of cytokines and antibodies to induce T cell polarization. The T cells were cultured in the presence or absence of 20 μM Apigenin. T-bet, IL-4, IL-17, and FoxP3 mRNA expression was detected by qPCR and compared to appropriate control (left). Culture supernatants were extracted and cytokines TNF-α, IL-17, IL-4, and TGF-β levels were detected by ELISA (right). Each data point is representative of 2 individual experiments with two replicates (PDF 119 kb)
Supplementary Figure 2
Reduced RelB expression in EAE and naïve mouse splenocytes. Splenocytes from EAE and naïve mice were stimulated with and without MOG35–55 peptide for 3 days in the presence or absence of 20 μM Apigenin. Cells were pelleted, and RNA was extracted using the TRIzol method followed by cDNA preparation and qPCR. A) RelB mRNA expression compared to β-Actin and normalized to cells that were not treated with MOG35–55 peptide. Naïve T cells that were polarized as described in Fig. 5 were analyzed for RelB mRNA expression in the Th1, Th2 and Th17 subsets. B) RelB mRNA expression compared to β-Actin and normalized to the Th0 subset. Sample standard error (SE) is shown and statistical significance was determined by Student’s t test. (**p < 0.01). (PDF 41 kb)
Supplementary Figure 3
RelB silencing does not potentiate Apigenin effect in immature DCs. DCs were isolated as in Fig. 1 followed by treatment with 20 μM Apigenin. 25 nM siRNA directed against RelB was transfected in to DCs. sip65 was used as positive control. Changes in DC phenotype were determined by flow cytometry. Figures show FACS plot of cell surface markers expressed on DCs. (PDF 309 kb)
Supplementary Figure 4
RelB silencing does not significantly modulate differentiation of Th2 cells. DCs and autologous PBLs from 3 donors were treated as described in Fig. 8. Enumeration of the Th2 cell subset upon both RelB knockdown and Apigenin treatment is shown. Statistical significance was determined by 2-way ANOVA using Sidak’s test for multiple comparisons. (PDF 44 kb)
Supplementary Figure 5
RelB silencing increases numbers of Tregs cultured in the presence of Apigenin treated immature DCs. DCs were isolated as described. DCs were treated with 20 μM Apigenin or left untreated. 25 nM siRelB was transfected in to DCs. sip65 was used as positive control. Following transfection DCs were co-cultured with autologous PBLs for 6d as described. FACS plots describe T cell subset polarization in presence of immature DCs treated/untreated with Apigenin. (PDF 977 kb) (PDF 465 kb)
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Ginwala, R., Bhavsar, R., Moore, P. et al. Apigenin Modulates Dendritic Cell Activities and Curbs Inflammation Via RelB Inhibition in the Context of Neuroinflammatory Diseases. J Neuroimmune Pharmacol 16, 403–424 (2021). https://doi.org/10.1007/s11481-020-09933-8
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DOI: https://doi.org/10.1007/s11481-020-09933-8