Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene.
Transgenic mice expressing an inducible suicide gene, which allows systemic and reversible elimination of macrophages, were developed. A macrophage-specific c-fms promoter was used to express enhanced green fluorescent protein and a drug-inducible suicide gene that leads to Fas-mediated apoptosis in resting and cycling cells of the macrophage lineage. Transgenic mice were fertile, of normal weight, and showed no abnormal phenotype before drug exposure. The transgene was expressed constitutively in macrophages and dendritic cells (DC) but not significantly in T cells or B cells. Induction of the suicide gene led to depletion of 70-95% of macrophages and DC in nearly all tissues examined. Depletion reduced the ability to clear bacteria from the blood and led to increased bacterial growth in the liver. Depleted mice displayed several abnormalities, including splenomegaly, lymphadenopathy, thymic atrophy, extramedullary hematopoiesis, and development of peritoneal adhesions. This new, transgenic line will be useful in investigating the role of macrophages and DC.
Burnett
Sandra H
SH
Department of Microbiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0084, USA.
Kershen
Edward J
EJ
Zhang
Jiayou
J
Zeng
Li
L
Straley
Susan C
SC
Kaplan
Alan M
AM
Cohen
Donald A
DA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D002452:Cell Count; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019281:Dimerization; D004195:Disease Models, Animal; D041722:Genes, Transgenic, Suicide / Q000187:drug effects / Q000235:genetics*; D049452:Green Fluorescent Proteins; D007111:Immunity, Cellular / Q000235:genetics; D008164:Luminescent Proteins; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000235:genetics; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D019014:fas Receptor / Q000235:genetics*
C463061:AP20187; D008164:Luminescent Proteins; D017475:Receptors, Nerve Growth Factor; D019014:fas Receptor; D049452:Green Fluorescent Proteins; D016186:Receptor, Macrophage Colony-Stimulating Factor; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus