There is growing evidence that sphingosine-1-phosphate (S1P), a pleiotropic bioactive sphingolipid metabolite synthesized intracellularly by two closely related sphingosine kinases (SphKs), SphK1 and SphK2, is involved in inflammation. However, the role of SphKs/S1P/S1P receptors (S1PRs) in autoimmune thyroiditis (AIT) has not been studied to date.
Methods:
This study examined whether SphK1/S1P/S1PR1 signaling is aberrantly altered in thyroid tissues and serum of both AIT patients and a spontaneously autoimmune thyroiditis (SAT) mouse model. Murine CD4+T cells were employed to further investigate the downstream signaling of SphK1/S1P/S1PR1. Furthermore, a total of 102 NOD.H-2h4 mice, randomly divided into different groups, were used to investigate the therapeutic effect of S1PR1 blockade and its potential mechanism.
Results:
We found that components of the SphK1/S1P/S1PR1 pathway were abnormally expressed in patients with Hashimoto thyroiditis and in a SAT mouse model. In addition, S1P could activate signal transducer and activator of transcription 3 (STAT3) through S1PR1 and its downstream signaling pathways in CD4+T cells of NOD.H-2h4 mice. Furthermore, an in vivo study demonstrated that blocking S1PR1 by FTY720 administration could reduce the incidence and severity of thyroiditis and goiter in SAT mice in a time-dependent manner. The proportions of STAT3-related and inflammation-related cell subtypes, such as T helper 1, T helper 17, and follicular T helper cells, were elevated in the SAT group when compared to the control group, and these cell subtypes decreased after FTY720 administration. Furthermore, the downstream inflammatory cytokines of STAT3 were also downregulated after FTY720 administration.
Conclusion:
The present study shows that blocking Sphk1/S1P/S1PR1 signaling can ameliorate the severity of AIT, providing evidence of a promising therapeutic target for AIT.
Get full access to this article
View all access options for this article.
References
1.
ShanZ, ChenL, LianX, LiuC, ShiB, ShiL, TongN, WangS, WengJ, ZhaoJ, TengX, YuX, LaiY, WangW, LiC, MaoJ, LiY, FanC, TengW. 2016. Iodine status and prevalence of thyroid disorders after introduction of mandatory universal salt iodization for 16 years in China: a cross-sectional study in 10 cities. Thyroid, 26:1125–1130.
2.
ShiX, HanC, LiC, MaoJ, WangW, XieX, XuB, MengT, DuJ, ZhangS, GaoZ, ZhangX, FanC, ShanZ, TengW. 2015. Optimal and safe upper limits of iodine intake for early pregnancy in iodine-sufficient regions: a cross-sectional study of 7190 pregnant women in China. J Clin Endocrinol Metab, 100:1630–1638.
3.
TengW, ShanZ, TengX, GuanH, LiY, TengD, JinY, YuX, FanC, ChongW, YangF, DaiH, YuY, LiJ, ChenY, ZhaoD, ShiX, HuF, MaoJ, GuX, YangR, TongY, WangW, GaoT, LiC. 2006. Effect of iodine intake on thyroid diseases in China. N Engl J Med, 354:2783–2793.
4.
WangW, XueH, LiY, HouX, FanC, WangH, ZhangH, ShanZ, TengW. 2015. Effects of selenium supplementation on spontaneous autoimmune thyroiditis in NOD.H-2(h4) mice. Thyroid, 25:1137–1144.
5.
ZhaoW, HanC, ShiX, XiongC, SunJ, ShanZ, TengW. 2014. Prevalence of goiter and thyroid nodules before and after implementation of the universal salt iodization program in mainland China from 1985 to 2014: a systematic review and meta-analysis. PLoS One, 9:e109549.
LiuT, SunJ, WangZ, YangW, ZhangH, FanC, ShanZ, TengW. 2017. Changes in the DNA methylation and hydroxymethylation status of the intercellular adhesion molecule 1 gene promoter in thyrocytes from autoimmune thyroiditis patients. Thyroid, 27:838–845.
13.
HanC, HeX, XiaX, LiY, ShiX, ShanZ, TengW. 2015. Subclinical hypothyroidism and type 2 diabetes: a systematic review and meta-analysis. PLoS One, 10:e0135233.
14.
WangX, LiuH, ZhangY, LiJ, TengX, LiuA, YuX, ShanZ, TengW. 2015. Effects of isolated positive maternal thyroglobulin antibodies on brain development of offspring in an experimental autoimmune thyroiditis model. Thyroid, 25:551–558.
15.
LiC, PengS, LiuX, HanC, WangX, JinT, LiuS, WangW, XieX, HeX, ZhangH, ShanL, FanC, ShanZ, TengW. 2017. Glycyrrhizin, a direct HMGB1 antagonist, ameliorates inflammatory infiltration in a model of autoimmune thyroiditis via inhibition of TLR2-HMGB1 signaling. Thyroid, 27:722–731.
16.
LiuX, MaoJ, HanC, PengS, LiC, JinT, FanC, ShanZ, TengW. 2016. CXCR4 antagonist AMD3100 ameliorates thyroid damage in autoimmune thyroiditis in NOD.H2h(4) mice. Mol Med Rep, 13:3604–3612.
WangW, XueH, LiY, HouX, FanC, WangH, ZhangH, ShanZ, TengW. 2015. Effects of selenium supplementation on spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. Thyroid, 25:1137–1144.
22.
RadhikaA, JacobSS, SudhakaranPR. 2007. Influence of oxidatively modified LDL on monocyte-macrophage differentiation. Mol Cell Biochem, 305:133–143.
23.
GuoQ, WuD, YuH, BaoJ, PengS, ShanZ, GuanH, TengW. 2018. Alterations of global DNA methylation and DNA methyltransferase expression in T and B lymphocytes from patients with newly diagnosed autoimmune thyroid diseases after treatment: a follow-up study. Thyroid, 28:377–385.
24.
QinJ, ZhouJ, FanC, ZhaoN, LiuY, WangS, CuiX, HuangM, GuanH, LiY, ShanZ, TengW. 2017. Increased circulating Th17 but decreased CD4(+)Foxp3(+) Treg and CD19(+)CD1d(hi)CD5(+) Breg subsets in new-onset Graves' disease. Biomed Res Int, 2017:8431838.
25.
PengS, LiC, WangX, LiuX, HanC, JinT, LiuS, ZhangX, ZhangH, HeX, XieX, YuX, WangC, ShanL, FanC, ShanZ, TengW. 2016. Increased toll-like receptors activity and TLR ligands in patients with autoimmune thyroid diseases. Front Immunol, 7:578.
26.
TaylorSC, PoschA. 2014. The design of a quantitative western blot experiment. Biomed Res Int, 2014:361590.
27.
HanC, WuW, AleA, KimMS, CaiD. 2016. Central leptin and tumor necrosis factor-alpha (TNFalpha) in diurnal control of blood pressure and hypertension. J Biol Chem, 291:15131–15142.
28.
YangX, GaoT, ShiR, ZhouX, QuJ, XuJ, ShanZ, TengW. 2014. Effect of iodine excess on Th1, Th2, Th17, and Treg cell subpopulations in the thyroid of NOD.H-2h4 mice. Biol Trace Elem Res, 159:288–296.
29.
StaabJ, BarthPJ, MeyerT. 2012. Cell-type-specific expression of STAT transcription factors in tissue samples from patients with lymphocytic thyroiditis. Endocr Pathol, 23:141–150.
30.
PengD, TanikawaT, LiW, ZhaoL, VatanL, SzeligaW, WanS, WeiS, WangY, LiuY, StaroslawskaE, SzubstarskiF, RolinskiJ, GrywalskaE, StanislawekA, PolkowskiW, KurylcioA, KleerC, ChangAE, WichaM, SabelM, ZouW, KryczekI. 2016. Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling. Cancer Res, 76:3156–3165.
31.
RavichandranKS. 2011. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity, 35:445–455.
PitsonSM, MorettiPA, ZebolJR, LynnHE, XiaP, VadasMA, WattenbergBW. 2003. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J, 22:5491–5500.
34.
ChenK, WeiY, SharpGC, Braley-MullenH. 2007. Decreasing TNF-alpha results in less fibrosis and earlier resolution of granulomatous experimental autoimmune thyroiditis. J Leukoc Biol, 81:306–314.
35.
XuC, WuF, MaoC, WangX, ZhengT, BuL, MouX, ZhouY, YuanG, WangS, XiaoY. 2016. Excess iodine promotes apoptosis of thyroid follicular epithelial cells by inducing autophagy suppression and is associated with Hashimoto thyroiditis disease. J Autoimmun, 75:50–57.
36.
WangSH, BakerJR. 2007. The role of apoptosis in thyroid autoimmunity. Thyroid, 17:975–979.
37.
FangY, Braley-MullenH. 2008. Cultured murine thyroid epithelial cells expressing transgenic Fas-associated death domain-like interleukin-1beta converting enzyme inhibitory protein are protected from fas-mediated apoptosis. Endocrinology, 149:3321–3329.
38.
PengS, YuX, ZhaoX, WangX, SunX, HanC, ShanZ, LiC, TengW. 2017. Role of the tumour necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) axis in autoimmune thyroid disease. Clin Endocrinol (Oxf), 87:783–790.
39.
SekiguchiM, IwasakiT, KitanoM, KunoH, HashimotoN, KawahitoY, AzumaM, HlaT, SanoH. 2008. Role of sphingosine 1-phosphate in the pathogenesis of Sjogren's syndrome. J Immunol, 180:1921–1928.
40.
KulakowskaA, Zendzian-PiotrowskaM, BaranowskiM, KononczukT, DrozdowskiW, GorskiJ, BuckiR. 2010. Intrathecal increase of sphingosine 1-phosphate at early stage multiple sclerosis. Neurosci Lett, 477:149–152.
41.
InokiK, OuyangH, LiY, GuanKL. 2005. Signaling by target of rapamycin proteins in cell growth control. Microbiol Mol Biol Rev, 69:79–100.
42.
YangF, ZhangW, LiD, ZhanQ. 2013. Gadd45a suppresses tumor angiogenesis via inhibition of the mTOR/STAT3 protein pathway. J Biol Chem, 288:6552–6560.
43.
KapposL, RadueEW, O'ConnorP, PolmanC, HohlfeldR, CalabresiP, SelmajK, AgoropoulouC, LeykM, Zhang-AubersonL, BurtinP. 2010. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med, 362:387–401.
TsunemiS, IwasakiT, KitanoS, ImadoT, MiyazawaK, SanoH. 2010. Effects of the novel immunosuppressant FTY720 in a murine rheumatoid arthritis model. Clin Immunol, 136:197–204.
49.
ZhangJX, ZhangJ, YanW, WangYY, HanL, YueX, LiuN, YouYP, JiangT, PuPY, KangCS. 2013. Unique genome-wide map of TCF4 and STAT3 targets using ChIP-seq reveals their association with new molecular subtypes of glioblastoma. Neuro Oncol, 15:279–289.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
