CD44-deficiency on hematopoietic cells limits T-cell number but does not protect against atherogenesis in LDL receptor-deficient mice.
OBJECTIVE
Vascular and inflammatory cells express adhesion molecule CD44. We demonstrated previously that enhanced CD44 localizes in human atherosclerotic lesions. Apolipoprotein E/cd44 double-deficient mice and apolipoprotein E-deficient mice transplanted with CD44-deficient bone marrow (BM) exhibit reduced atherosclerosis. Since CD44 is a novel factor in atherogenesis, it is imperative that it is investigated in more than one animal model to conclusively determine its role in this particular disease pathology. To test the hypothesis that CD44 expressed by hematopoietic cells plays a critical role in atherogenesis in the low density lipoprotein (LDL) receptor-deficient mouse model, we performed BM reconstitution experiments.


METHODS
Lethally irradiated LDL receptor-deficient mice were transplanted with either CD44-deficient or wild-type BM. Beginning 10 weeks after successful reconstitution, mice consumed a cholesterol-enriched atherogenic diet for 6 or 11 weeks.


RESULTS
Surprisingly, CD44-deficiency on BM-derived inflammatory cells did not affect lesion size. Additionally, neither group displayed differences in smooth muscle cell, macrophage, collagen, or elastin content as well as lipoprotein levels. However, lesions in CD44-deficient BM-recipient mice contained fewer T-cells compared to wild-type BM mice. Interestingly, CD44-deficient T-cells expressed less chemokine receptor-5 mRNA. Furthermore, in vivo leukocyte adhesion decreased in CD44-deficient mice compared to wild-type mice.


CONCLUSIONS
This study surprisingly revealed that atherogenesis does not require CD44 expression on hematopoietic cells in the LDL receptor-deficient mouse model. However, CD44 promotes T-cell recruitment, downregulates chemokine receptor-5, and participates critically in leukocyte adhesion in vivo. Consequently, the anti-atherogenic role of CD44 may require CD44-deficiency on cell types other than inflammatory cells in the LDL receptor-deficient mouse model.
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Sara
S
Sjöberg
Einar E
EE
Eriksson
Asa
A
Tivesten
Annelie
A
Carlsson
Anna
A
Klasson
Max
M
Levin
Jan
J
Borén
Alexandra
A
Krettek
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002448:Cell Adhesion; D004036:Diet, Atherogenic; D005260:Female; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics*; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D019713:Receptors, CCR5 / Q000096:biosynthesis; D011973:Receptors, LDL / Q000172:deficiency; D000685:Serum Amyloid A Protein / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D001057:Apolipoproteins E; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D019713:Receptors, CCR5; D011973:Receptors, LDL; D000685:Serum Amyloid A Protein