Neutrophils in polytrauma – from recruitment to phenotypic and functional reprogramming

Abstract: My long-term goal is to determine the mechanisms that regulate neutrophil response in health and disease and how they are altered by the presence of chronic low-grade systemic inflammation. Traumatic injuries are a leading cause of death and disability in younger people being a major public health problem worldwide. Neutrophils are known for their fast and moldable inflammatory response upon injury, which are massively recruited after trauma. Neutrophils play a crucial pathological role in the complex systemic inflammatory response that leads to life-threaten situations. Patients with chronic low-grade systemic "metabolic" inflammation display a dysregulated neutrophil response and function. Consequently, these patients are at high risk of developing serious complications and exhibit a high mortality rate after trauma. Knowledge of how metainflammation impacts neutrophil response in polytrauma is limited, particularly in what concerns the regulatory mechanisms that coordinate and direct neutrophil recruitment to sites of concurrent traumatic injuries. Trauma affects the phenotype and function of neutrophils, which impairs the neutrophil capacity to fight infections while at the same time promotes tissue damage phenotypes that contribute to the overall immune dysfunction. These alterations on neutrophil populations set the stage for secondary inflammatory complications such as sepsis, multiple organ failure (MOF), and nosocomial infections that delay recovery and can lead to disability or death. It is also unclear how traumatic injury sites reprogrammed neutrophils and if it is dependent of trauma localization, or the patient’s overall inflammatory status. In this MIRA application, we plan to investigate mechanisms involved in neutrophil phenotypic and functional modulation in polytrauma. We will take advantage of the remarkable zebrafish animal model known for its optical transparency and ease of genetic and pharmacological manipulation to visualize, track and deconvolute the molecular mechanism involved in the neutrophil response in polytrauma at a whole-animal context. We will combine our zebrafish polytrauma model and unique whole-animal non-invasive live imaging approach with genetic manipulation and protein, lipid, transcript, and epigenetic profiling of neutrophils and concurrent traumatic injury sites to evaluate 1) the regulatory mechanisms that coordinate neutrophil recruitment to concurrent traumatic injuries, 2) how neutrophils are reprogrammed at sites of traumatic injury to generate specific neutrophil subsets that reverse migrate and disseminate inflammation in trauma, and 3) how chronic inflammation impacts such processes. Our research will allow us to gain a deeper understanding of the neutrophil mechanisms involved in polytrauma inflammatory response in healthy and metainflammation settings. The knowledge achieved by the proposed research will enable us to manipulate neutrophil response as a means by which to improve patient outcomes following trauma, particularly in high-risk groups.