Hematopoietic sphingosine 1-phosphate lyase deficiency decreases atherosclerotic lesion development in LDL-receptor deficient mice.

Martine Bot,Peter J Van Santbrink,Ilze Bot,Niels Nijstad,Marion J Gijbels,Theo J C Van Berkel,Georg Varga,Jason Johnson,Jerzy-Roch Nofer,Uwe J F Tietge,Carsten Müller-Tidow,Paul P Van Veldhoven,Marijke M Westra,Johan Kuiper,Gerd Van Der Hoeven,Erik A L Biessen,Saskia C A De Jager

doi:10.1371/journal.pone.0063360

Abstract

AimsAltered sphingosine 1-phosphate (S1P) homeostasis and signaling is implicated in various inflammatory diseases including atherosclerosis. As S1P levels are tightly controlled by S1P lyase, we investigated the impact of hematopoietic S1P lyase (Sgpl1−/−) deficiency on leukocyte subsets relevant to atherosclerosis.Methods and ResultsLDL receptor deficient mice that were transplanted with Sgpl1−/− bone marrow showed disrupted S1P gradients translating into lymphopenia and abrogated lymphocyte mitogenic and cytokine response as compared to controls. Remarkably however, Sgpl1−/− chimeras displayed mild monocytosis, due to impeded stromal retention and myelopoiesis, and plasma cytokine and macrophage expression patterns, that were largely compatible with classical macrophage activation. Collectively these two phenotypic features of Sgpl1 deficiency culminated in diminished atherogenic response.ConclusionsHere we not only firmly establish the critical role of hematopoietic S1P lyase in controlling S1P levels and T cell trafficking in blood and lymphoid tissue, but also identify leukocyte Sgpl1 as critical factor in monocyte macrophage differentiation and function. Its, partly counterbalancing, pro- and anti-inflammatory activity spectrum imply that intervention in S1P lyase function in inflammatory disorders such as atherosclerosis should be considered with caution.

Highlights

The lysosphingolipid sphingosine 1-phosphate (S1P) is an important lipid mediator generated from sphingosine upon cell activation and present in plasma and extracellular fluid at high nanomolar concentration [1,2]
Partly counterbalancing, pro- and anti-inflammatory activity spectrum imply that intervention in S1P lyase function in inflammatory disorders such as atherosclerosis should be considered with caution
To induce hematopoietic deficiency of S1P lyase, lethally irradiated LDLr2/2 mice were reconstituted with either Sgpl12/2 bone marrow or bone marrow isolated from wild type littermates

Summary

Introduction

The lysosphingolipid sphingosine 1-phosphate (S1P) is an important lipid mediator generated from sphingosine upon cell activation and present in plasma and extracellular fluid at high nanomolar concentration [1,2]. S1P gradients between lymphoid organs with low S1P concentration and the circulation, which contains high S1P levels, are a driving force for lymphocyte fluxes [7,11]. The actual regulation of S1P gradients remains elusive, as most cell types are able to generate S1P through ubiquitously expressed sphingosine kinases 1 and 2 [12,13], and degrade it through S1P lyase or S1P phosphatases 1 and 2 [1]. In addition to its contribution to lymphocyte trafficking, S1P plays a major role in endothelial integrity and confers protection against tumor necrosis factor (TNF)-a-induced monocyte-endothelial interactions [14,15]. S1P or analogues thereof are known to inhibit apoptosis in monocytes and bone marrow-derived macrophages [16] and to polarize macrophages towards less inflammatory alternatively activated phenotype [17]

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Results

Conclusion