Immunological function of sphingosine 1-phosphate in the intestine

Abstract

It has been shown that dietary materials are involved in immune regulation in the intestine. Lipids mediate immune regulation through a complex metabolic network that produces many kinds of lipid mediators. Sphingosine-1-phosphate (S1P) is a lipid mediator that controls cell trafficking and activation. In this review, we focus on the immunological functions of S1P in the regulation of intestinal immune responses such as immunoglobulin A production and unique T cell trafficking, and its role in the development of intestinal immune diseases such as food allergies and intestinal inflammation, and also discuss the relationship between dietary materials and S1P metabolism.

Keywords: IgA antibody; food allergy; intestinal immunity; intraepithelial T lymphocytes; lipid.

Figure 1

Dietary sphingolipids in epithelial-cell S1P production. Dietary sphingomyelin is degraded into ceramide and subsequently sphingosine by alkaline sphingomyelinase and ceramidase, respectively, which are expressed on the apical membranes of epithelial cells. In the epithelial cells, absorbed ceramide is metabolized into sphingosine. Together with absorbed sphingosine, sphingosine kinase metabolizes sphingosine into S1P, which then participates in immune regulation in the intestine.

Figure 2

Sequential changes in S1P1 expression during B-cell differentiation in Peyer’s patches. Dendritic cells (DC) take the antigens transported by M cells from intestinal lumen and present them to T cells for their activation. Through the interaction with T cells and DCs, IgM⁺ naive B cells show class-switch from IgM to IgA. During this process, S1P1 is expressed at high levels in IgM⁺ naive B cells and downregulated on B cells class-switching from IgM to IgA and subsequently recovered on IgA⁺ B220⁻ plasmablasts, resulting in their emigration from the Peyer’s patches and traffic into the intestinal lamina propria.

Figure 3

Distinct dependency on S1P in T-cell trafficking into the colonic epithelium. In the thymus, CD4⁻ CD8⁻ double-negative (DN) thymocytes differentiate into CD4⁺ CD8⁺ double-positive (DP) thymocytes and then into single-positive (SP) thymocytes expressing either CD4 or CD8 and αβTCR. These SP thymocytes express high levels of S1P1 and migrate out from the thymus and into the colon in an S1P-dependent manner. DN thymocytes express TCRαβ or TCRγδ. DN thymocytes expressing TCRαβ are derived from CD4⁺ CD8αα⁺ CD8αβ⁺ triple-positive (TP) thymocytes differentiated from DN or DP thymocytes. Little or no S1P1 expression is noted in the DN thymocytes expressing TCRαβ or TCRγδ, so traffic to the colonic epithelium proceeds in an S1P-independent manner.

Figure 4

S1P mediates intestinal allergy by regulating pathogenic T and mast cell infiltration into the colon. In murine food allergy model, systemically sensitized T cells migrate into the colon upon the oral challenge with same allergen. This trafficking is mediated by S1P and thus treatment with FTY720 resulted in the inhibition of activated T cell trafficking into the colon. In the colon, these activated T cells produced high amounts of Th2 cytokines such as IL-4 and IL-5 for promotion of mast cell recruitment and proliferation. In addition, mast cell itself expresses S1P1. Therefore, FTY720 treatment directly and indirectly (Th2 cytokine from activated T cells) decreases the numbers of mast cells in the colon. These effects lead to the inhibition of allergic diarrhea.