The NR4A subfamily of nuclear receptors consists of three mammalian members: Nur77, Nurr1, and NOR-1. The NR4A receptors are involved in essential physiological processes such as adaptive and innate immune cell differentiation, metabolism and brain function. They act as transcription factors that directly modulate gene expression, but can also form trans-repressive complexes with other transcription factors. In contrast to steroid hormone nuclear receptors such as the estrogen receptor or the glucocorticoid receptor, no ligands have been described for the NR4A receptors. This lack of known ligands might be explained by the structure of the ligand-binding domain of NR4A receptors, which shows an active conformation and a ligand-binding pocket that is filled with bulky amino acid side-chains. Other mechanisms, such as transcriptional control, post-translational modifications and protein-protein interactions therefore seem to be more important in regulating the activity of the NR4A receptors. For Nur77, over 80 interacting proteins (the interactome) have been identified so far, and roughly half of these interactions has been studied in more detail. Although the NR4As show some overlap in interacting proteins, less information is available on the interactome of Nurr1 and NOR-1. Therefore, the present review will describe the current knowledge on the interactomes of all three NR4A nuclear receptors with emphasis on Nur77.

SummaryActivation of macrophages by inflammatory stimuli induces reprogramming of mitochondrial metabolism to support the production of pro-inflammatory cytokines and nitric oxide. Hallmarks of this metabolic rewiring are downregulation of α-ketoglutarate formation by isocitrate dehydrogenase (IDH) and accumulation of glutamine-derived succinate, which enhances the inflammatory response via the activity of succinate dehydrogenase (SDH). Here, we identify the nuclear receptor Nur77 (Nr4a1) as a key upstream transcriptional regulator of this pro-inflammatory metabolic switch in macrophages. Nur77-deficient macrophages fail to downregulate IDH expression and accumulate higher levels of succinate and other TCA cycle-derived metabolites in response to inflammatory stimulation in a glutamine-independent manner. Consequently, these macrophages produce more nitric oxide and pro-inflammatory cytokines in an SDH-dependent manner. In vivo, bone marrow Nur77 deficiency exacerbates atherosclerosis development and leads to increased circulating succinate levels. In summary, Nur77 induces an anti-inflammatory metabolic state in macrophages that protects against chronic inflammatory diseases such as atherosclerosis.

Rationale: The alarmin S100A9 has been identified as a potential therapeutic target in myocardial infarction (MI). Short-term S100A9 blockade during the inflammatory phase post-MI inhibits systemic and cardiac inflammation and improves cardiac function long-term. Objective: To evaluate the impact of S100A9 blockade on post-ischemic cardiac repair. Methods and Results: We assessed cardiac function, hematopoietic response, and myeloid phagocyte dynamics in wild-type C57BL/6 mice with permanent coronary artery ligation, treated with the specific S100A9 blocker ABR-238901 for 7 or 21 days. In contrast to the beneficial effects of short-term therapy, extended S100A9 blockade led to progressive deterioration of cardiac function and left ventricle dilation. The treatment reduced the proliferation of Lin - Sca-1 + c-Kit + (LSK) haematopoietic stem and progenitor cells in the bone marrow, and the production of pro-reparatory CD150 + CD48-CCR2 + haematopoietic stem cells. Monocyte trafficking from the spleen to the myocardium and subsequent phenotype switching to reparatory Ly6C lo MerTK hi macrophages was also impaired, leading to inefficient efferocytosis, accumulation of apoptotic cardiomyocytes and a larger myocardial scar. The transcription factor Nur77 (Nr4a1) mediates the transition from inflammatory Ly6C hi monocytes to reparatory Ly6C lo macrophages. S100A9 upregulated the levels and activity of Nur77 in monocytes and macrophages in-vitro and in Ly6C hi/int monocytes in-vivo, and S100A9 blockade antagonised these effects. Finally, the presence of reparatory macrophages in the myocardium was also impaired in S100A9 -/- mice with permanent myocardial ischemia, leading to depressed cardiac function long-term. Conclusions: We show that S100A9 plays an important role in both the inflammatory and the reparatory immune responses to MI. Long-term S100A9 blockade negatively impacts cardiac recovery and counterbalances the beneficial effects of short-term therapy. These results define a therapeutic window targeting the inflammatory phase for optimal effects of S100A9 blockade as potential immunomodulatory treatment in acute MI.