Targeting NR4A Nuclear Receptors to Control Stromal Cell Inflammation, Metabolism, Angiogenesis, and Tumorigenesis

Abstract

The NR4A1–NR4A3 (Nur77, Nurr1, and Nor-1) subfamily of nuclear receptors is a group of immediate early genes induced by a pleiotropy of stimuli including peptide hormones, growth factors, cytokines, inflammatory, and physiological stimuli, and cellular stress. NR4A receptors function as potent sensors of changes in the cellular microenvironment to control physiological and pathological processes through genomic and non-genomic actions. NR4A receptors control metabolism and cardiovascular and neurological functions and mediate immune cell homeostasis in inflammation and cancer. This receptor subfamily is increasingly recognized as an important molecular connection between chronic inflammation, altered immune cell responses, and cancer development. In this review, we examine how transcriptome analysis identified NR4A1/NR4A2 receptors as transcriptional regulators in mesenchymal stromal cell (MSC) migration, cell cycle progression, and cytokine production to control local immune responses. In chronic inflammatory conditions, such as rheumatoid arthritis, NR4A receptors have been shown to modify the activity of MSC and fibroblast-like stromal cells to regulate synovial tissue hyperplasia, pathological angiogenesis, and cartilage turnover in vivo. Additionally, as NR4A1 has been observed as a major transcriptional regulator in tumor–stromal communication controlling tumorigenesis, we discuss how advances in the pharmacological control of these receptors lead to important new mechanistic insights into understanding the role of the tumor microenvironment in health and disease.

Bladder Exposure to Gardnerella Activates Host Pathways Necessary for Escherichia coli Recurrent UTI

“…Five genes were significantly increased (FDR adjusted P < 0.05, log 2 FC > 1.6) following the first Gardnerella exposure ( Figure 3 and Supplemental Table 8 ), and no genes withstood FDR correction after the second Gardnerella exposure. Notably, all of the upregulated genes ( Atf3 , Fosb , Nur77, Nurr1 and Arc ) belong to the class of Immediate Early (IE) response genes that are rapidly co-induced in multiple cell types in response to external stimuli, such as infection and inflammatory signals ( Wilson et al., 2010 ; Bahrami and Drablos, 2016 ; Crean and Murphy, 2021 ). This suggests that the presence of these genes in the dataset was not random or artifactual, but reflects a coordinated rapid response to Gardnerella exposure.…”

Ellagic Acid Alleviates Rheumatoid Arthritis in Rats through Inhibiting MTA1/HDAC1-Mediated Nur77 Deacetylation

“…For instance, NR4A1 reactivation by its agonist cytosporone B could inhibit IL-1 β induced chondrocyte inflammation, and injection of cytosporone B protected cartilage damage and alleviated osteoarthritis in rat osteoarthritis model [ 24 ]. More importantly, current available research elucidated that NR4A receptors modified the activity of FLSs to regulate synovial tissue hyperplasia, pathological angiogenesis, and cartilage turnover [ 25 ], which indicated that Nur77 might be involved in the progression of RA. Besides, Nur77 was identified as an acetylated protein, and HDAC1 decreased the acetylation level, transcriptional activity, and protein level of Nur77 [ 15 ].…”

The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

“…Notably, steroid receptors may modify enzymes and ion channels independent of transcriptional activation, namely, nongenomic effects [ 94 ]. Besides metabolic regulation through binding to multiple hormones, NRs also widely impact the embryonic development and maturation of several organ systems, signaling control in proliferation, and reproduction [ 95 ].…”