Shift of cell-death mechanisms in primary human neutrophils with a ruthenium photosensitizer

Abstract: Primary human neutrophils are the most abundant human white blood cells and are central for innate immunity. They act as early responders at inflammation sites, guided by chemotactic gradients to find infection or inflammation sites. Neutrophils can undergo both apoptosis as well as NETosis. NETosis is a form of neutrophil cell death that releases chromatin-based extracellular traps (NETs) to capture and neutralize pathogens. Understanding or controlling the balance between these cell-death mechanisms is crucial. In this study, the chemical synthesis and biologic assessment of a ruthenium complex as a light-activated photosensitizer that creates reactive oxygen species (ROS) in primary human neutrophils is reported. The ruthenium complex remains non-toxic in the dark. However, upon exposure to blue light at 450 nm, it exhibits potent cytotoxic effects in both cancerous and non-cancerous cell lines. Interestingly, the metal complex shifts the cell-death mechanism of primary human neutrophils from NETosis to apoptosis. Cells irradiated directly by the light source immediately undergo apoptosis, whereas those further away from the light source perform NETosis at a slower rate. This indicates that high ROS levels trigger apoptosis and lower ROS levels NETosis. The ability to control the type of cell death undergone in primary human neutrophils could have implications in managing acute and chronic infectious diseases.