NR4A nuclear receptor expression in human macrophages mediates apoptosis and controls <i>Mycobacterium tuberculosis</i> growth

Tuberculosis (TB), a significant global health issue, needs novel therapeutic approaches to reduce its burden. Studying host-pathogen interactions provides new targets for host-directed therapeutics (HDTs). Nuclear receptors (NRs) are important master regulators of cellular function and bona fide drug targets. Herein, we identify high basal expression of the NR4A NR family in human alveolar macrophages and determine that all 3 members (NR4A1, NR4A2, and NR4A3) are upregulated in response to Mycobacterium tuberculosis (M.tb) infection. NR4A expression was also increased in our recently developed human alveolar macrophage-like (AML) cell model compared to monocyte-derived macrophages. We investigated the role of the NR4As in apoptosis given its importance in controlling M.tb growth. NR4A small interfering RNA knockdown in AML cells prior to their treatment with apoptosis-inducing compounds resulted in reduced caspase-3/7 activity, indicating reduced apoptosis. Additionally, knockdown prior to M.tb infection resulted in reduced apoptosis of AML cells and increased M.tb growth. Treatment of AML cells with NR4A ligands significantly reduced M.tb growth while treatment with an NR4A antagonist significantly increased it. In conclusion, we identify the expression, location, and apoptotic activity of NR4A NRs in human macrophages and their potential as new TB HDT therapeutic targets.