Abstract
Aims: Altered 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 (Sgpl12/2) deficiency on leukocyte subsets relevant to atherosclerosis.
Methods and Results: LDL receptor deficient mice that were transplanted with Sgpl12/2 bone marrow showed disrupted
S1P gradients translating into lymphopenia and abrogated lymphocyte mitogenic and cytokine response as compared to
controls. Remarkably however, Sgpl12/2 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.
Conclusions: Here 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.
including atherosclerosis. As S1P levels are tightly controlled by S1P lyase, we investigated the impact of hematopoietic S1P
lyase (Sgpl12/2) deficiency on leukocyte subsets relevant to atherosclerosis.
Methods and Results: LDL receptor deficient mice that were transplanted with Sgpl12/2 bone marrow showed disrupted
S1P gradients translating into lymphopenia and abrogated lymphocyte mitogenic and cytokine response as compared to
controls. Remarkably however, Sgpl12/2 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.
Conclusions: Here 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.
| Original language | English |
|---|---|
| Pages (from-to) | e63360 |
| Number of pages | 13 |
| Journal | PLoS ONE |
| Volume | 8 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2013 |