Sphk1/S1P/S1PR1 Signaling is Involved in the Development of Autoimmune Thyroiditis in Patients and NOD.H-2h4 Mice

Background: 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.