Sphingosine-1-phosphate alleviates colitis by regulating macrophage polarization and PI3k-Akt signaling

Liang Hu¹Zi Yang¹Ying Zhang¹Conglin Du¹Yang Yang¹Zhichao Chang¹Xiangchun Li^2*Zhaochen Shan^1*

• ¹Beijing Stomatological Hospital, Capital Medical University, Beijing, China
• ²Department of Stomatology, the First Hospital of Qinhuangdaohu, Qinhuangdao, China

Introduction: Inflammatory bowel disease (IBD) is a complex disease that is characterized by tight junction loss and dysregulation of immune homeostasis. The repair of intestinal integrity and immune function in IBD remains a clinical challenge. Sphingosine-1-phosphate (S1P) has been reported to alleviate radiation-induced salivary gland damage by maintaining epithelial integrity. However, its potential to restore function during IBD has not yet been investigated. Methods: Dextran sulfate sodium (DSS) was added to the drinking water of C57BL/6 mice for 5 days to induce colitis. Subsequently, S1P and vehicle were injected intravenously on days 1, 3, and 5. Body weight, the disease activity index (DAI), and the histological activity index (HAI) were recorded. The level of apoptosis and expression of tight junction proteins among the groups were compared. We explored the underlying mechanisms of S1P using RNA sequencing. Results: S1P alleviated DSS-induced colitis by suppressing inflammatory cell infiltration, reducing ulcers, and maintaining intestinal epithelial junction integrity by increasing E-cadherin and occludin expression. S1P decreased apoptosis, promoted macrophage M1 polarization, and suppressed M2 polarization. RNA sequencing revealed upregulation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt) and chemokine signaling pathways in the DSS group compared with those in the S1P group. Conclusions: S1P alleviated colitis by promoting and suppressing macrophage M2 and M1 polarization, respectively, and regulating PI3K/Akt signaling.