NR4A1 (Nur77) is an orphan nuclear receptor that functions as a transcription factor to regulate inflammation and cell survival. NR4A1 belongs to the NR4A family of nuclear receptors that also includes NR4A2 (Nurr1) and NR4A3 (NOR-1). NR4A1 is expressed in monocytes and macrophages and is found within atherosclerotic lesions. We discovered in 2011 that NR4A1 functions as a key transcription factor to regulate development of the Ly6C- monocyte lineage in bone marrow. Ly6C- monocytes possess patrolling functions to survey the vasculature to initiate rapid innate immune responses. In this proposal, we hypothesize that NR4A1 is a critical transcription factor in the bone marrow required for the proliferation of the Ly6C- monocyte subset. Furthermore, we propose that patrolling monocytes function to protect against atherosclerosis development by regulating host defense and inflammatory responses. We have 3 specific aims:
Aim 1 will determine whether NR4A1 regulates the production and homeostasis of monocytes in bone marrow through regulation of cell cycle gene expression.
Aim 2 will determine whether NR4A1 expression in monocytes promotes resolution of inflammation.
Aim 3 will determine whether the absence of patrolling monocytes promotes atherosclerosis progression in vivo. Our discoveries reveal a novel role for NR4A1 in regulation of monocyte differentiation from bone marrow progenitors, which has implication for multiple inflammatory and immune-mediated diseases, including atherosclerosis. As monocytes are mobilized from bone marrow in response to pathogens in a TLR-dependent manner, NR4A1 may also play an important role in host defense during an early innate immune response. Thus, identifying mechanisms for how NR4A1 regulates monocyte production in bone marrow and its impact on atherosclerosis is highly significant, as this NR4A class of nuclear receptors can be targeted pharmacologically.
Monocytes serve as a first line of defense in innate and adaptive immune reactions. They are rapidly recruited to sites of injury or inflammation. NR4A1 (Nur77) is an orphan nuclear receptor that functions as a transcription factor to regulate monocyte development. In this proposal we will identify how NR4A1 regulates monocyte production in bone marrow as well as identify the function of NR4A1 in regulating inflammatory responses of macrophages in atherosclerosis.
|Park, Kiwon; Mikulski, Zbigniew; Seo, Goo-Young et al. (2016) The transcription factor NR4A3 controls CD103+ dendritic cell migration. J Clin Invest 126:4603-4615|
|Thomas, Graham; Tacke, Robert; Hedrick, Catherine C et al. (2015) Nonclassical patrolling monocyte function in the vasculature. Arterioscler Thromb Vasc Biol 35:1306-16|
|Hanna, Richard N; Cekic, Caglar; Sag, Duygu et al. (2015) Patrolling monocytes control tumor metastasis to the lung. Science 350:985-90|
|Gerhardt, Teresa; Ley, Klaus (2015) Monocyte trafficking across the vessel wall. Cardiovasc Res 107:321-30|
|Nowyhed, Heba N; Huynh, Tridu R; Thomas, Graham D et al. (2015) Cutting Edge: The Orphan Nuclear Receptor Nr4a1 Regulates CD8+ T Cell Expansion and Effector Function through Direct Repression of Irf4. J Immunol 195:3515-9|
|Nowyhed, Heba N; Huynh, Tridu R; Blatchley, Amy et al. (2015) The nuclear receptor nr4a1 controls CD8 T cell development through transcriptional suppression of runx3. Sci Rep 5:9059|
|Tacke, Robert; Hilgendorf, Ingo; Garner, Hannah et al. (2015) The transcription factor NR4A1 is essential for the development of a novel macrophage subset in the thymus. Sci Rep 5:10055|
|Shaked, Iftach; Hanna, Richard N; Shaked, Helena et al. (2015) Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation. Nat Immunol 16:1228-34|
|Hanna, Richard N; Hedrick, Catherine C (2014) Stressing out stem cells: linking stress and hematopoiesis in cardiovascular disease. Nat Med 20:707-8|
|Hamers, Anouk A J; Hanna, Richard N; Nowyhed, Heba et al. (2013) NR4A nuclear receptors in immunity and atherosclerosis. Curr Opin Lipidol 24:381-5|