Endogenous regulation mechanisms of NET formation

The immune system defends the body against pathogens and cancer, but when dysregulated it can harm the host. A telling example is the production of neutrophil extracellular traps (NETs), a response of immune cells that confers antimicrobial protection in health but that can also participate in worsening the condition of diseased individuals. NETs are web-like structures that trap and effectively prevent the spread of viruses, bacteria, fungi, and parasites. They contain molecules that kill pathogens but that can also damage the surrounding host tissue. This is observed in individuals infected with SARS- CoV2 where NETs entrap the virus but damage the alveoli thus contributing to acute lung injury. Likewise, NETs are a contributing factor in numerous inflammatory and autoimmune pathologies and cancer. In the past two decades, scientists have made great leaps in understanding how NETs are formed and how they act in health and disease. It is nevertheless unclear how the body fine-tunes such a tightly controlled response. Our previous work showed, for the first time, that neutrophils undergoing NET formation release molecules that drive the process. My project will investigate this novel aspect of NET generation, i.e. its regulation by endogenous molecules. Using several techniques, we will identify which endogenous NET inducers are the most critical because they represent potential therapeutic targets. We will furthermore characterize how these endogenous molecules are released and how neutrophils respond to them over time. We will additionally test whether other immune cells release endogenous NET inducers. These experiments will shed light on how the NET response is endogenously modulated. By uncovering the fine-tuning of NET formation, we hope to advance the development of improved treatment options for patients with numerous NET-related diseases including metastatic cancer, rheumatoid arthritis, inflammatory bowel disease, lupus, and several pulmonary ailments.