Gelatin enhances bacteria-phagocytosis via a ROS-mitochondria-STING axis in differentiated human macrophage-like U937...

The recruitment of macrophages to a pathological site is accompanied by the change in surrounding extracellular matrix. The pathological foci in a highly inflammatory status contain certain amounts of gelatin, the denatured form of collagen. We previously revealed that precoating the cell dishes with gelatin, but not type I collagen, enhances bacteria-phagocytosis capacity of phorbol 12-myristate 13-acetate (PMA)-treated macrophage-like human histiocytic lymphoma U937 cells. The present study further reveals that gelatin-precoating increases the amount of reactive oxygen species (ROS) in PMA-treated U937 cells, which contributes to the enhanced phagocytosis of bacteria, including both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. ROS in cells on gelatin-precoated culture plates cause impairments on mitochondria, as shown by the reduced mitochondrial membrane potential and ATP levels, as well as the increase in oxidative lesions in mitochondrial DNA. These mitochondrial damages lead to the activation of stimulator of interferon genes (STING) pathway, which enhances the bacteria-phagocytosis in PMA-treated U937 cells. Simultaneously, mitophagy-related proteins, such as PINK1, parkin and LC3 II, all increase following the elevation of ROS levels. Of note, mitophagy restricts the mitochondrial disorders, forming a feedback negative regulation for the effects of ROS, and works against bacteria-phagocytosis. This study reveals a core function of ROS-mitochondria-STING axis during gelatin-enhanced bacteria-phagocytosis in PMA-stimulated macrophage-like U937 cells, and provides possibility for clinically applying gelatin as a protectant for bacterial infection in some lesions.