Incomplete Inhibition of Sphingosine 1-Phosphate Lyase Modulates Immune System Function yet Prevents Early Lethality and Non-Lymphoid Lesions

Abstract

BackgroundS1PL is an aldehyde-lyase that irreversibly cleaves sphingosine 1-phosphate (S1P) in the terminal step of sphingolipid catabolism. Because S1P modulates a wide range of physiological processes, its concentration must be tightly regulated within both intracellular and extracellular environments.MethodologyIn order to better understand the function of S1PL in this regulatory pathway, we assessed the in vivo effects of different levels of S1PL activity using knockout (KO) and humanized mouse models.Principal FindingsOur analysis showed that all S1PL-deficient genetic models in this study displayed lymphopenia, with sequestration of mature T cells in the thymus and lymph nodes. In addition to the lymphoid phenotypes, S1PL KO mice (S1PL−/−) also developed myeloid cell hyperplasia and significant lesions in the lung, heart, urinary tract, and bone, and had a markedly reduced life span. The humanized knock-in mice harboring one allele (S1PLH/−) or two alleles (S1PLH/H) of human S1PL expressed less than 10 and 20% of normal S1PL activity, respectively. This partial restoration of S1PL activity was sufficient to fully protect both humanized mouse lines from the lethal non-lymphoid lesions that developed in S1PL−/− mice, but failed to restore normal T-cell development and trafficking. Detailed analysis of T-cell compartments indicated that complete absence of S1PL affected both maturation/development and egress of mature T cells from the thymus, whereas low level S1PL activity affected T-cell egress more than differentiation.SignificanceThese findings demonstrate that lymphocyte trafficking is particularly sensitive to variations in S1PL activity and suggest that there is a window in which partial inhibition of S1PL could produce therapeutic levels of immunosuppression without causing clinically significant S1P-related lesions in non-lymphoid target organs.

Sphingosine-1–Phosphate, FTY720, and Sphingosine-1–Phosphate Receptors in the Pathobiology of Acute Lung Injury

“…In Sgpl1 1/2 mice, LPS challenge increased lethality, serum concentrations of TNF-a, monocyte chemotactic protein 1 (MCP-1), and IL-6, and sphingoid bases compared with Sgpl1 1/1 mice (57), suggesting a detrimental effect of high-circulating S1P concentrations. The genetic and chemical inhibition of S1PL with the inhibitors 2-acetyl-4 (5)-[1R,2S,3R,4-tetrahydroxybutyl]-imidazole (THI) and LX2931 increased circulating and tissue S1P concentrations, reduced peripheral lymphocytes, and alleviated inflammatory responses in animal models of autoimmunity (58). A complete deficiency of S1PL in mice resulted in lesions in the lung, heart, urinary system, and bone, as well as T-cell depletion in the blood, thymus, spleen, and lymph nodes, which was attributed to very high circulating S1P concentrations (58).…”

Identification of acyl-CoA synthetases involved in the mammalian sphingosine 1-phosphate metabolic pathway

“…Since the S1P metabolic pathway is the sole pathway allowing conversion of the LCB portion of sphingolipids to acyl-CoAs and further to glycerophospholipids, its failure to function may lead to aberrant sphingolipid homeostasis. Indeed, knockout mice for the Spl (Sgpl1) gene, which encodes S1P lyase that catalyzes the first, irreversible step of the S1P metabolic pathway, have a pleiotropic phenotype, including abnormal lipid homeostasis in the liver, brain, and adipose tissue, myeloid cell hyperplasia, skeletal and hematological dysfunctions, and lesions in the lung, heart, urinary tract, and bone, and these mice die approximately one month after birth [4,5].…”

Sphingosine‐1‐phosphate signaling in physiology and diseases

“…SPL-KO mice display markedly high levels of S1P in tissues and serum with accumulation of ceramide and long chain bases, resulting in multi-organ damages with pro-inflammatory responses and altered lymphocyte and neutrophil distribution [21,22].…”