NR4A Receptors in Immunity: Bridging Neuro-Endocrine and Inflammatory Pathways

Nuclear receptors (NRs) are ligand-activated transcription factors that mediate diverse cellular processes, including signalling, survival, proliferation, immune response and metabolism, through both genomic and non-genomic mechanisms in response to hor-mones and metabolic ligands. Given their central role in inter-organ, tissue, and cellular communication, NRs are critical for maintaining homeostasis and have become a major focus in biomedical research and drug discovery due to their association with numerous diseases. Among NRs, the NR4A subfamily (NR4A1/Nur77, NR4A2/Nurr1, and NR4A3/Nor1) re-sponds to various stimuli—such as insulin, growth factors, inflammatory cytokines, and β-adrenergic signals—though their endogenous ligands remain unidentified. Their ex-pression is tissue-dependent, particularly in energy-demanding tissues, where they mod-ulate leukocyte function and promote an anti-inflammatory profile. Like other NRs, NR4As regulate acute and chronic inflammation by suppressing pro-inflammatory tran-scription factors (e.g., NF-κB) or enhancing their inhibitors, thereby polarising macro-phages toward an anti-inflammatory phenotype. This review summarises current knowledge on the role of NR4A receptors in immune re-sponses. Given their well-documented involvement in autoimmune diseases, inflammato-ry conditions, and cancer, elucidating their contributions to neuro-immune-endocrine crosstalk may uncover their therapeutic potential for immunopathological disorders.