Abstract 1487: CD44 on Bone Marrow-Derived Cells Limits T-Cell Recruitment But is Not Required for Atherogenesis in LDL Receptor-Deficient Mice
Adhesion molecule CD44, expressed by vascular and inflammatory cells, is implicated as novel player in atherogenesis. We previously demonstrated enhanced CD44 in human atherosclerosis. Others have shown that Apolipoprotein E/CD44 double-deficient mice exhibit 70% lesion reduction. However, the importance of various cell types as sources of CD44 remains unknown. To test the hypothesis that CD44 expressed on hematopoietic cells is crucial to atherogenesis, we performed bone marrow (BM) reconstitution experiments. Lethally irradiated LDL receptor-deficient (Ldlr−/−) mice were transplanted with either CD44-deficient or wild-type BM. Ten weeks after successful reconstitution, mice consumed cholesterol-rich (Paigen) diet for 6 or 11 weeks. We found that 94 ± 2% wild-type (n=26) and 93 ± 2% CD44-deficient (n=32) BM repopulated recipient mice. Thus, CD44-deficient BM exhibits homing, despite current notion that proper migration/homing of hematopoietic cells requires CD44. Surprisingly, CD44-deficiency on BM-derived cells did not affect size or lesion composition. Only a trend was observed towards less lesions after 6 (37%, n=18; P=0.166) and 11 weeks (16%, n=15; P=0.097) of diet-induced atherosclerosis in en face aortas of CD44-deficient compared to wild-type BM recipient mice. Neither smooth muscle cell and macrophage content nor lipoprotein profiles differed between groups. Interestingly, lesions in CD44-deficient BM recipient mice (n=16) exhibited less CD8- and CD4-positive T-cells (55.6 ± 8.4 T-cells/mm2) than mice that carried wild-type BM (n=12, 100.7 ± 7.5 T-cells/mm2; P=0.001). CD44 deficiency is accompanied by 30% reduction of chemokine receptor 5 (CCR5) expression (n=8; P<0.05); a potential mechanism for T-cell reduction in CD44-deficient BM reconstituted mice, since CCR5 has been implicated in T-cell recruitment. In conclusion, homing of hematopoietic cells is not limited to CD44 expression. This study surprisingly revealed that CD44 expression on hematopoietic cells is not required for the anti-atherogenic effect seen by systemic lack of CD44. However, CD44 deficiency of hematopoietic cells limits T-cell recruitment. Consequently, the anti-atherogenic role of CD44 may require absence of CD44 on vascular cell types.