NR4A NUCLEAR RECEPTORS AS REGULATORS OF THE MACROPHAGE RESPONSE TO MYCOBACTERIUM TUBERCULOSIS: FROM PATIENT EXPRESSION TO A PUTATIVE NR4A1/NLRP3 AXIS

Mycobacterium tuberculosis (MTB) infection drives a persistent, harmful macrophage response central to tuberculosis (TB) immunopathology. NR4A nuclear receptors (NR4A1/Nur77, NR4A2/Nurr1, NR4A3/NOR-1) are orphan, ligand-dependent transcription factors acting as early inflammatory sensors, with hydrophobic pockets showing affinity for lipid ligands. We previously showed that all three NR4A members are upregulated in blood of TB patients in a severity-dependent manner, alongside an immunoendocrine imbalance (increased cortisol, IL-6, IL-10, IFN-γ; decreased DHEA). In THP-1-derived M1/M2 macrophages stimulated with irradiated MTB (MTBi), NR4A, NF-κB pathway and cytokine transcripts were differentially modulated by polarization state, with NR4A3 tracking NFKB1, NFKBIA and IL-10 in MTBi-treated M1 cells, suggesting a compensatory anti-inflammatory role. By immunoblotting, MTBi significantly increased phosphorylated (active) NR4A1 in M2 macrophages, and immunofluorescence localized phosphorylated NR4A1 to the perinuclear region in this condition, consistent with interaction with subcellular structures. Preliminary molecular docking (AutoDock Vina) showed favourable predicted binding energies between MTB lipids and all three NR4A receptors, with NR4A1 -particularly its dimeric form- showing the highest affinity. Since NR4A1 and the NLRP3 inflammasome both respond to lipid signals -i.e. the mycobacterial glycolipid trehalose dimycolate is a validated NLRP3 activator- and can localize to perinuclear membranes during inflammation, this convergence raises the possibility of a functional link between them in MTB-stimulated M2 macrophages, a hypothesis that warrants further experimental testing. Overall, our findings support a context-dependent, polarization-specific role for NR4A receptors, particularly NR4A1, in the macrophage response to MTB, encouraging further work on their potential as host-directed therapeutic targets in TB.