Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis.
BACKGROUND: Sphingosine-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...
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doaj-07686167d0cf451ba24a1d1bcb253d4f2020-11-25T01:38:24ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0183e5963010.1371/journal.pone.0059630Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis.Andreas BillichThomas BaumrukerChristian BeerliMarc BigaudChristian BrunsThomas CalzasciaAndrea IskenBernd KinzelErika LoetscherBarbara MetzlerMatthias MuellerBarbara Nuesslein-HildesheimBernadette Kleylein-SohnBACKGROUND: Sphingosine-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. METHODOLOGY: We 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 FINDINGS: The 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. SIGNIFICANCE: The data suggest Sgpl1 as a novel therapeutic target for the treatment of multiple sclerosis.http://europepmc.org/articles/PMC3609791?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andreas Billich Thomas Baumruker Christian Beerli Marc Bigaud Christian Bruns Thomas Calzascia Andrea Isken Bernd Kinzel Erika Loetscher Barbara Metzler Matthias Mueller Barbara Nuesslein-Hildesheim Bernadette Kleylein-Sohn |
spellingShingle |
Andreas Billich Thomas Baumruker Christian Beerli Marc Bigaud Christian Bruns Thomas Calzascia Andrea Isken Bernd Kinzel Erika Loetscher Barbara Metzler Matthias Mueller Barbara Nuesslein-Hildesheim Bernadette Kleylein-Sohn Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis. PLoS ONE |
author_facet |
Andreas Billich Thomas Baumruker Christian Beerli Marc Bigaud Christian Bruns Thomas Calzascia Andrea Isken Bernd Kinzel Erika Loetscher Barbara Metzler Matthias Mueller Barbara Nuesslein-Hildesheim Bernadette Kleylein-Sohn |
author_sort |
Andreas Billich |
title |
Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis. |
title_short |
Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis. |
title_full |
Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis. |
title_fullStr |
Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis. |
title_full_unstemmed |
Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis. |
title_sort |
partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
description |
BACKGROUND: Sphingosine-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. METHODOLOGY: We 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 FINDINGS: The 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. SIGNIFICANCE: The data suggest Sgpl1 as a novel therapeutic target for the treatment of multiple sclerosis. |
url |
http://europepmc.org/articles/PMC3609791?pdf=render |
work_keys_str_mv |
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