Bone marrow NR4A expression is not a dominant factor in the development of atherosclerosis or macrophage polarization in mice.

Chao L, Soto E, Hong C, Ito A, Pei L, Chawla A, Conneely O, Tangirala RK, Evans RM, Tontonoz P.

The formation of the atherosclerotic lesion is a complex process influenced by an array of inflammatory and lipid metabolic pathways. We previously demonstrated that NR4A nuclear receptors are highly induced in macrophages in response to inflammatory stimuli and modulate the expression of genes linked to inflammation in vitro. Here we used mouse genetic models to assess the impact of NR4A expression on atherosclerosis development and macrophage polarization. Transplantation of wild-type, Nur77-/- or Nor1-/- null hematopoetic precursors into LDLR-/- recipient mice led to comparable development of atherosclerotic lesions after high-cholesterol diet. We also observed comparable induction of genes linked to M1 and M2 responses in wild-type and Nur77-null macrophages in response to lipopolysaccharide and IL-4, respectively. In contrast, activation of the nuclear receptor LXR strongly suppressed M1 responses, and ablation of STAT6 strongly suppressed M2 responses. Recent studies have suggested that alterations in levels of Ly6Clo monocytes may be a contributor to inflammation and atherosclerosis. In our study, loss of Nur77, but not Nor1, was associated with decreased abundance of Ly6Clo monocytes, but this change was not correlated with atherosclerotic lesion development. Collectively, our results suggest that alterations in the Ly6Clo monocyte population and bone marrow NR4A expression do not play dominant roles in macrophage polarization or the development of atherosclerosis in mice.

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January, 2013



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