Abstract
BackgroundSphingosine-1-phosphate (S1P) regulates the egress of T cells from lymphoid organs; levels of S1P in the tissues are controlled by S1P lyase (Sgpl1). Hence, Sgpl1 offers a target to block T cell-dependent inflammatory processes. However, the involvement of Sgpl1 in models of disease has not been fully elucidated yet, since Sgpl1 KO mice have a short life-span.MethodologyWe generated inducible Sgpl1 KO mice featuring partial reduction of Sgpl1 activity and analyzed them with respect to sphingolipid levels, T-cell distribution, and response in models of inflammation.Principal FindingsThe partially Sgpl1 deficient mice are viable but feature profound reduction of peripheral T cells, similar to the constitutive KO mice. While thymic T cell development in these mice appears normal, mature T cells are retained in thymus and lymph nodes, leading to reduced T cell numbers in spleen and blood, with a skewing towards increased proportions of memory T cells and T regulatory cells. The therapeutic relevance of Sgpl1 is demonstrated by the fact that the inducible KO mice are protected in experimental autoimmune encephalomyelitis (EAE). T cell immigration into the CNS was found to be profoundly reduced. Since S1P levels in the brain of the animals are unchanged, we conclude that protection in EAE is due to the peripheral effect on T cells, leading to reduced CNS immigration, rather than on local effects in the CNS.SignificanceThe data suggest Sgpl1 as a novel therapeutic target for the treatment of multiple sclerosis.
Highlights
Sphingosine-1-phosphate (S1P) is a pluripotent lipid signaling molecule with important functions in health and disease across a broad range of organ systems [1,2,3,4]
To generate inducible Sgpl1 KO mice, the floxed Sgpl1 mice were crossed with a B6.C actbCreERT2 knock-in mouse line [28]; breeding yielded Sgpl1Flox/ Flox Cre+/2 ( = inducible KO) and Sgpl1Flox/Flox Cre2/2 ( = control) littermates, which were used for experimentation
Sgpl1Flox/FloxCre+/2 mice were treated with tamoxifen for 5 days to induce Sgpl1 knock-out; two weeks later, deletion of exon 8 was observed with a frequency of 70–90% in the genomic DNA of various tissues, with the notable exception of brain (,40%) (Fig. 1A)
Summary
Sphingosine-1-phosphate (S1P) is a pluripotent lipid signaling molecule with important functions in health and disease across a broad range of organ systems [1,2,3,4]. As opposed to interfering with the molecular targets of S1P, modulation of its concentration constitutes an alternative approach to capture the therapeutic benefit of inhibiting or enhancing the functions of S1P. This appears achievable in at least three different ways: (i) by using anti-S1P antibodies to reduce extracellular S1P [10]; (ii) by inhibiting or enhancing the activity of intracellular sphingosine kinases which produce S1P [11,12]; (iii) by blocking S1P-degrading enzymes, namely the S1P phosphatases or S1P lyase [13]. The involvement of Sgpl in models of disease has not been fully elucidated yet, since Sgpl KO mice have a short life-span
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