Pseudomonas quinolone signal (PQS) is a quorum-sensing molecule associated with Pseudomonas aeruginosa that regulates quorum sensing, extracellular vesicle biogenesis,
iron acquisition, and the secretion of
virulence factors. PQS has been shown to have immunomodulatory effects on the host. It induces oxidative stress, modulates
cytokine levels, and activates regulated cell death in the host. In this study, we investigated the effects of PQS (10 μM) on host organelle dynamics and dysfunction in human macrophages at the interphase of endoplasmic reticulum (ER), mitochondria, and lysosome. This study showed that PQS increases cytosolic Ca+2 levels and elevates ER stress, as evidenced by increased expression of BiP and activation of the PERK-CHOP axis of unfolded protein response (UPR). Moreover, PQS also negatively affects mitochondria by disrupting mitochondrial membrane potential and increasing mitochondrial ROS generation (mROS). Additionally, PQS stimulation decreased the number of
acridine orange-positive lysosomes, indicating lysosomal destabilization. Furthermore, PQS-induced lysosomal destabilization also induces overexpression of the lysosomal stress-responsive gene TFEB. Besides organelle dysfunction, PQS dysregulates
inflammation-related genes by upregulating NLRC4, TMS1, and
Caspase 1 while downregulating NLRP3 and IL-1β. Also, PQS increases gene expression of pro-inflammatory
cytokines (IL-6, TNF-α, and IFN-γ). In conclusion, our findings suggest that PQS negatively affects human macrophages by interfering with organelle function and dysregulating inflammatory response. Consequently, this study provides crucial insight into PQS-driven macrophage dysfunction and may contribute to a better understanding of Pseudomonas aeruginosa-associated
infections.