Deficiency of the NR4A Orphan Nuclear Receptor NOR1 in Hematopoietic Stem Cells Accelerates Atherosclerosis

Abstract

Objective The NR4A orphan nuclear receptor NOR1 functions as a constitutively active transcription factor regulating cellular inflammation and proliferation. In the present study, we employed bone marrow transplantation to determine the selective contribution of NOR1 expression in hematopoietic stem cells to the development of atherosclerosis. Methods and Results Reconstitution of lethally irradiated apoE−/− mice with NOR1-deficient hematopoietic stem cells accelerated atherosclerosis formation and macrophage recruitment following feeding a diet enriched in saturated fat. NOR1 deficiency in hematopoietic stem cells induced splenomegaly and monocytosis, specifically the abundance of inflammatory Ly6C+ monocytes. Bone marrow transplantation studies further confirmed that NOR1 suppresses the proliferation of macrophage and dendritic progenitor (MDP) cells. Expression analysis identified RUNX1, a critical regulator of hematopoietic stem cell expansion, as a target gene suppressed by NOR1 in MDP cells. Finally, in addition to inducing Ly6C+ monocytosis, NOR1 deletion increased the replicative rate of lesional macrophages and induced local foam cell formation within the atherosclerotic plaque. Conclusion Collectively, our studies demonstrate that NOR1 deletion in hematopoietic stem cells accelerates atherosclerosis formation by promoting myelopoiesis in the stem cell compartment and by inducing local pro-atherogenic activities in the macrophage, including lesional macrophage proliferation and foam cell formation.

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

“…Moreover, macrophage NOR1 seems to play a protective role in atherogenesis, since it inhibits the inflammatory response of macrophages as well as their ability to transform into foam-cells [15]. In line with this observation, NOR1 deletion in hematopoietic cells accelerates atherosclerosis progression by increasing macrophage infiltration and proliferation in atherosclerotic lesions [21]. Moreover, expression of NOR1 has been recently described in murine mast cells, where it controls the cell response to allergens [22].…”

The pro‐inflammatory effect of NR4A3 in osteoarthritis

“…Furthermore, another study of vascular smooth muscle cells also indicated a different result . However, other NR4A3 studies have obtained different results as well, such as Qing H et al, who reported that haematopoietic cell‐specific NR4A3 knockout (KO) accelerates atherosclerosis with monocytosis, while full NR4A3 KO mice showed decreased atherosclerosis according to another study, suggesting that NR4A3 possesses cell‐specific function.…”

“…The first study on NR4A3 focused on neurons; NR4A3‐deficient mice showed defects in their inner ear development . Study of its function in atherosclerosis showed that haematopoietic cell–specific NR4A3 knockout induced atherosclerosis . Other researchers also identified that NR4A3 is involved in vascular remodelling and arterial disease .…”

The transcription factor NR4A3 controls CD103+ dendritic cell migration

“…Nr4a3 has been shown to play an important role in cell survival and proliferation in nonhematopoietic cells (20,21). Nr4a3 expression in monocytes is probably antiatherogenic (22). In lymphocytes, Nr4a3 is involved in the negative selection of T cells, together with Nr4a1 (23).…”