title: 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 Ly6C(lo) monocytes may be a contributor to inflammation and atherosclerosis. In our study, loss of Nur77, but not Nor1, was associated with decreased abundance of Ly6C(lo) monocytes, but this change was not correlated with atherosclerotic lesion development. Collectively, our results suggest that alterations in the Ly6C(lo) monocyte population and bone marrow NR4A expression do not play dominant roles in macrophage polarization or the development of atherosclerosis in mice.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.
authors.forename: Lily C
authors.initials: LC
authors.lastname: Chao
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, CA.
authors.forename: Erin
authors.initials: E
authors.lastname: Soto
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Ito
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, CA.
authors.forename: Liming
authors.initials: L
authors.lastname: Pei
authors.affiliation: Cardiovascular Research Institute, Departments of Physiology and Medicine, University of California at San Francisco, San Francisco, CA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Chawla
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
authors.forename: Orla M
authors.initials: OM
authors.lastname: Conneely
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Tangirala
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, CA; Howard Hughes Medical Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA; Howard Hughes Medical Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D057105:Nuclear Receptor Subfamily 4, Group A, Member 1