Sphingosine-1-phosphate analogue FTY720 causes lymphocyte redistribution and hypercholesterolemia in ApoE-deficient mice.
OBJECTIVE
Resident immune cells are a hallmark of atherosclerotic lesions. The sphingolipid analogue drug FTY720 mediates retrafficking of immune cells and inhibits their homing to inflammatory sites. We have evaluated the effect of FTY720 on atherogenesis and lipid metabolism.


RESULTS
ApoE-/- mice on a normal laboratory diet received oral FTY720 for 12 weeks, which led to a 2.4-fold increase in serum cholesterol (largely VLDL fraction) and a 1.8-fold increase in hepatic HMGCoA reductase mRNA. FTY720 increased plasma sphingosine-1-phosphate and induced marked peripheral blood lymphopenia. A discoordinate modulation of B, T and monocyte cell numbers was found in peripheral lymphoid organs. Overall depletion of T cells was accompanied by a relative (2-fold) increase in regulatory T cell content paralleled by a similar increase in effector memory T cells (CD4+ CD44hi CD62lo) as absolute numbers of both subpopulations remained essentially unchanged. Lymphocyte function was unaltered as indicated by anti-OxLDL antibodies and T cell proliferation. There were no changes in atherosclerotic lesions in early and established atherosclerosis.


CONCLUSIONS
FTY720 mediated peripheral lymphocyte depletion and retrafficking without altering function and overall balance of pro- and antiatherogenic lymphocyte populations. A net decrease in lymphocyte numbers occurred concomitantly with a more proatherogenic hypercholesterolemia resulting in unaltered atherogenesis.
Klingenberg
Roland
R
Department of Cardiology, University Hospital Heidelberg, Germany. roland.klingenberg@ki.se
Nofer
Jerzy-Roch
JR
Rudling
Mats
M
Bea
Florian
F
Blessing
Erwin
E
Preusch
Michael
M
Grone
Hermann J
HJ
Katus
Hugo A
HA
Hansson
Göran K
GK
Dengler
Thomas J
TJ
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000276:immunology / Q000503:physiopathology; D000068876:Fingolimod Hydrochloride; D006937:Hypercholesterolemia / Q000139:chemically induced*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000187:drug effects; D008214:Lymphocytes / Q000097:blood / Q000187:drug effects; D008231:Lymphopenia / Q000139:chemically induced; D008246:Lysophospholipids / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D013154:Spleen / Q000187:drug effects / Q000276:immunology
D001057:Apolipoproteins E; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D011409:Propylene Glycols; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine