Low- but not high-dose FK506 treatment confers atheroprotection due to alternative macrophage activation and unaffected cholesterol levels.
Previous studies showed both pro- and anti-atherogenic effects of immunosuppressant drug FK506 on atherosclerosis. As these divergent/paradoxical results of FK506 may at least in part be attributable to differences in FK506 dosing, we have, in the current study, assessed dose-dependent effects of FK506 on atherosclerotic lesion formation as well as on inflammatory parameters relevant to atherosclerosis. Unlike low-dose FK506, high-dose FK506 did not protect against atherosclerosis in ApoE-/- mice. The high-dose induced hypercholesterolaemia, whereas the low-dose did not. Both low- and high-dose FK506 treatment significantly reduced systemic CD3+ and CD4+CD25+ T-cell populations, and showed similar suppression of FoxP3 regulatory T-cell populations. Increased IL-4+ CD4+ T-cells and decreased IgG-MDA-LDL antibody titres pointed to a selective, albeit modest Th2 skewing in the high-dose treatment group, despite the advanced stage of atherosclerosis. Low concentrations of FK506, however, skewed bone marrow-derived macrophage polarisation towards a M2 macrophage phenotype, whereas high concentration did not. A low-dose FK506 treatment regime protected against atherosclerosis by suppressing T-cell activation and favouring (M2) macrophage polarisation. Although a high-dose FK506 treatment effected a similar T-cell suppressive effect, with an even more pronounced shift towards Th2 type immune responses, this did not translate in atheroprotection due to the hypercholesterolaemia and absent M2 skewing.
Bai
Lili
L
Maastricht University Medical Center, P. Debyelaan 25, Maastricht, The Netherlands.
Gabriels
Karen
K
Wijnands
Erwin
E
Rousch
Mat
M
Daemen
Mat J A P
MJ
Tervaert
J W Cohen
JW
Biessen
Erik A L
EA
Heeneman
Sylvia
S
D000818:Animals; D000906:Antibodies / Q000097:blood; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D054796:Drug Dosage Calculations; D006801:Humans; D006937:Hypercholesterolemia / Q000209:etiology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D000906:Antibodies; D001057:Apolipoproteins E; D016207:Cytokines; D007166:Immunosuppressive Agents; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D016559:Tacrolimus