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

Abstract

The formation of the atherosclerotic lesion is a complex process influenced by an array of inflammatory and lipid metabolism 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 LDL receptor (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 lipopolysaccharides and interleukin (IL)-4, respectively. In contrast, activation of the nuclear receptor liver X receptor (LXR) strongly suppressed M1 responses, and ablation of signal transductor and activator of transcription 6 (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.

Limited Role of Nuclear Receptor Nur77 in Escherichia coli-Induced Peritonitis

“…Again, no differences were found between WT and Nur77 Ϫ/Ϫ macrophages in TNF-␣, KC, and IL-6 production or in mRNA expression of several cytokines and chemokines known to be upregulated in this model. These results are not in agreement with data reported previously by our group and others, in which macrophages were stimulated with LPS (10,(16)(17)(18). One explanation may be that LPS is only one of a whole range of antigens present on E. coli bacteria.…”

“…In atherosclerosis bone marrow, specific deletion of Nur77 aggravates the disease, with vascular lesions containing more macrophages, T cells, and chemokine SDF-1␣ (16,17). Of note, it was also recently described that Nur77 does not affect atherosclerosis (18). Hanna et al (19) demonstrated that Nur77 Ϫ/Ϫ mice lack the patrolling Ly6C lo monocyte population in bone marrow, spleen, and blood.…”

The neuron-derived orphan receptor 1 (NOR1) is induced upon human alternative macrophage polarization and stimulates the expression of markers of the M2 phenotype

“…Macrophages from Nur77À/À mice show modifications in the expression of M2-specific markers with a shift toward a pro-inflammatory phenotype, exhibiting increased expression of M1-markers such as interleukin-12, interferon-g and nitric oxide synthase [23,24]. However, these results have been challenged by another study showing that NOR1 and Nur77 are not dominant actors in M2 macrophage polarization in the mouse [25].…”

The Orphan Nuclear Receptor Nur77 Is a Determinant of Myofiber Size and Muscle Mass in Mice

“…Mice bearing the NOR1 mutant allele were mated as heterozygotes due to decreased fertility of the NOR1 Ϫ/Ϫ mice. Finally, we bred the MCK-Cre mouse (on a mixed C57BL/6J and C57BL/6N background) (catalog number 006475; The Jackson Laboratory) to the compound mutant to generate control ( Ϫ/Ϫ were reported elsewhere (25). Mice were fed ad libitum and maintained on a 12-h light-dark cycle and were age and gender matched for all experiments.…”