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Effects of deletion of macrophage ABCA7 on lipid metabolism and the development of atherosclerosis in the presence and absence of ABCA1.

Meurs I, Calpe-Berdiel L, Habets KL, Zhao Y, Korporaal SJ, Mommaas AM, Josselin E, Hildebrand RB, Ye D, Out R, Kuiper J, Van Berkel TJ, Chimini G, Van Eck M - PLoS ONE (2012)

Bottom Line: However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05).In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1.Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis.

View Article: PubMed Central - PubMed

Affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands.

ABSTRACT
ABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies. In the current study, we investigated the in vivo effects of macrophage ABCA7 deficiency on lipid metabolism and atherosclerosis. Chimeras with dysfunctional ABCA7 in macrophages and other blood cells were generated by transplantation of bone marrow from ABCA7 knockout (KO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice. Unexpectedly, macrophage ABCA7 deficiency did not significantly affect atherosclerosis susceptibility of LDLr KO mice after 10 weeks Western-type diet feeding. However, ABCA7 deficiency was associated with 2-fold (p<0.05) higher macrophage ABCA1 mRNA expression levels. Combined disruption of ABCA1 and ABCA7 in bone-marrow-derived cells increased atherosclerotic lesion development (1.5-fold (p>0.05) as compared to wild type transplanted mice. However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05). Macrophage foam cell accumulation in the peritoneal cavity was reduced in ABCA1/ABCA7 dKO transplanted animals as compared to single ABCA1 KO transplanted mice, which was associated with increased ABCG1 expression. Interestingly, spleens of ABCA1/ABCA7 double KO transplanted mice were significantly larger as compared to the other 3 groups and showed massive macrophage lipid accumulation, a reduction in CD3+ T-cells, and increased expression of key regulators of erythropoiesis. In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1. Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis. Our data indicate that ABCA7 may play a role in T cell proliferation and erythropoeisis in spleen.

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Effects of single macrophage ABCA7 and combined macrophage ABCA1 and ABCA7 deficiency on cellular spleen composition.Spleen cell subsets measured by flow cytometry expressed as percentage of positive cells. Values represent the mean ± SEM of 5 mice per group. Statistically significant difference *p<0.05, **p<0.01 and ***p<0.001.
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pone-0030984-g008: Effects of single macrophage ABCA7 and combined macrophage ABCA1 and ABCA7 deficiency on cellular spleen composition.Spleen cell subsets measured by flow cytometry expressed as percentage of positive cells. Values represent the mean ± SEM of 5 mice per group. Statistically significant difference *p<0.05, **p<0.01 and ***p<0.001.

Mentions: Cell subsets composition of the spleen was evaluated by determing mRNA expression of CD3, CD4, CD68, and CD19 (Fig. 7). ABCA7 KO transplanted mice exhibited increased splenic mRNA expression in T helper cells (CD4) compared to controls (p<0.01). No differences were observed in B cells (CD19) and macrophages (CD68) between the groups. Subsequently, the effect of combined deletion of ABCA1 and ABCA7 on splenic cell population was examined by FACS analysis (Fig. 8). Deletion of ABCA1 and/or ABCA7 did not affect splenic F4/80+ macrophages, CD19+ B cells, and CD4+/CD25high regulatory T cells compared to control mice. Single ABCA7 deficiency did show an increase in CD4+ T helper cells, which, however, failed to reach significance (29±0.4% compared with 25±0.5% in WT transplanted animals; p>0.05). This increase in CD4+ cells was in line with the increase in CD4 mRNA expression measured by qPCR analysis (Fig. 7). Remarkably, disruption of both ABCA1 and ABCA7 on hematopoietic cells resulted in a decrease in the percentage of splenic CD3+ T cells (22±3% compared with 39±4% in WT transplanted animals; p<0.01) (Fig. 8), which is the result of a trend towards a reduction in T helper cells (CD4+)(p>0.05) and a significant reduction in cytotoxic T cells (CD8+)(p<0.001). A decrease in splenic CD3+ T cells in dKO transplanted mice was also indicated by immunohistochemical staining against lymphocyte CD3 antigen (Fig. 6B). WT, ABCA1 KO, and ABCA7 KO transplanted mice showed strong CD3+ staining in the centre of white pulp areas of the spleen, which represents the periarterial lymphatic sheath (PALS). DKO transplanted mice, however, showed a disturbed spleen morphology, as the white and red pulp areas were difficult to distinguish from each other and no strong CD3+ staining could be observed, even not in the PALS. No effect was observed on lymphocyte counts in the circulation nor in the thymus and lymph nodes (data not shown), indicating that the observed effects on T cells are specific for spleen.


Effects of deletion of macrophage ABCA7 on lipid metabolism and the development of atherosclerosis in the presence and absence of ABCA1.

Meurs I, Calpe-Berdiel L, Habets KL, Zhao Y, Korporaal SJ, Mommaas AM, Josselin E, Hildebrand RB, Ye D, Out R, Kuiper J, Van Berkel TJ, Chimini G, Van Eck M - PLoS ONE (2012)

Effects of single macrophage ABCA7 and combined macrophage ABCA1 and ABCA7 deficiency on cellular spleen composition.Spleen cell subsets measured by flow cytometry expressed as percentage of positive cells. Values represent the mean ± SEM of 5 mice per group. Statistically significant difference *p<0.05, **p<0.01 and ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293875&req=5

pone-0030984-g008: Effects of single macrophage ABCA7 and combined macrophage ABCA1 and ABCA7 deficiency on cellular spleen composition.Spleen cell subsets measured by flow cytometry expressed as percentage of positive cells. Values represent the mean ± SEM of 5 mice per group. Statistically significant difference *p<0.05, **p<0.01 and ***p<0.001.
Mentions: Cell subsets composition of the spleen was evaluated by determing mRNA expression of CD3, CD4, CD68, and CD19 (Fig. 7). ABCA7 KO transplanted mice exhibited increased splenic mRNA expression in T helper cells (CD4) compared to controls (p<0.01). No differences were observed in B cells (CD19) and macrophages (CD68) between the groups. Subsequently, the effect of combined deletion of ABCA1 and ABCA7 on splenic cell population was examined by FACS analysis (Fig. 8). Deletion of ABCA1 and/or ABCA7 did not affect splenic F4/80+ macrophages, CD19+ B cells, and CD4+/CD25high regulatory T cells compared to control mice. Single ABCA7 deficiency did show an increase in CD4+ T helper cells, which, however, failed to reach significance (29±0.4% compared with 25±0.5% in WT transplanted animals; p>0.05). This increase in CD4+ cells was in line with the increase in CD4 mRNA expression measured by qPCR analysis (Fig. 7). Remarkably, disruption of both ABCA1 and ABCA7 on hematopoietic cells resulted in a decrease in the percentage of splenic CD3+ T cells (22±3% compared with 39±4% in WT transplanted animals; p<0.01) (Fig. 8), which is the result of a trend towards a reduction in T helper cells (CD4+)(p>0.05) and a significant reduction in cytotoxic T cells (CD8+)(p<0.001). A decrease in splenic CD3+ T cells in dKO transplanted mice was also indicated by immunohistochemical staining against lymphocyte CD3 antigen (Fig. 6B). WT, ABCA1 KO, and ABCA7 KO transplanted mice showed strong CD3+ staining in the centre of white pulp areas of the spleen, which represents the periarterial lymphatic sheath (PALS). DKO transplanted mice, however, showed a disturbed spleen morphology, as the white and red pulp areas were difficult to distinguish from each other and no strong CD3+ staining could be observed, even not in the PALS. No effect was observed on lymphocyte counts in the circulation nor in the thymus and lymph nodes (data not shown), indicating that the observed effects on T cells are specific for spleen.

Bottom Line: However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05).In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1.Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis.

View Article: PubMed Central - PubMed

Affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands.

ABSTRACT
ABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies. In the current study, we investigated the in vivo effects of macrophage ABCA7 deficiency on lipid metabolism and atherosclerosis. Chimeras with dysfunctional ABCA7 in macrophages and other blood cells were generated by transplantation of bone marrow from ABCA7 knockout (KO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice. Unexpectedly, macrophage ABCA7 deficiency did not significantly affect atherosclerosis susceptibility of LDLr KO mice after 10 weeks Western-type diet feeding. However, ABCA7 deficiency was associated with 2-fold (p<0.05) higher macrophage ABCA1 mRNA expression levels. Combined disruption of ABCA1 and ABCA7 in bone-marrow-derived cells increased atherosclerotic lesion development (1.5-fold (p>0.05) as compared to wild type transplanted mice. However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05). Macrophage foam cell accumulation in the peritoneal cavity was reduced in ABCA1/ABCA7 dKO transplanted animals as compared to single ABCA1 KO transplanted mice, which was associated with increased ABCG1 expression. Interestingly, spleens of ABCA1/ABCA7 double KO transplanted mice were significantly larger as compared to the other 3 groups and showed massive macrophage lipid accumulation, a reduction in CD3+ T-cells, and increased expression of key regulators of erythropoiesis. In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1. Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis. Our data indicate that ABCA7 may play a role in T cell proliferation and erythropoeisis in spleen.

Show MeSH
Related in: MedlinePlus