Effect of reconstitution with Nfkb1^tm1Bal homozygous hematopoietic cells on atherogenesis in atherosclerosis prone mice

To assess the role of NFKB1 in atherogenesis, mice homozygous for a mutation of the low density lipoprotein receptor (Ldlr^tm1Her) were lethally irradiated and transplanted with bone marrow from Nfkb1^tm1Bal homozygous mice and 4 weeks later placed on a high-fat diet for 10 weeks. Aortic root lesion area of mice with NFKB1-deficient hematopoietic cells was 41% smaller than in control mice. Whereas control lesions contained primarily large foam cells, lesions of mice reconstituted with NFKB1-deficient bone marrow contained large numbers of small, inflammatory cells and very few foam cells. 3-fold as many cells attached to the lesion cap in transplanted mice. Most cells in control lesions were macrophages, while in transplanted mice there was a preponderance of T and B lymphocytes.

Macrophages induced to differentiate in culture from NFKB1-deficient bone marrow exhibited differences compared to control macrophages in the secretion patterns of several cytokines following lipopolysaccharide (LPS) stimulation. Whereas control macrophages expressed high levels of scavenger receptor class A (SR-A) in response to LPS, this response was greatly attenuated in mice with NFKB1-deficient hematopoietic systems; uptake of oxidized low density lipoprotein (oxLDL) was similarly diminished, although neither parameter differed between transplant and control macrophages in the absence of stimulation. J:87639