Neutrophils are the most abundant leukocyte in the blood, known for their fast and moldable inflammatory response upon injury. These innate immune cells are mostly known by their "dark side" due to their role in immunopathology of numerous human diseases; however, neutrophils also have a "light side" supporting vital functions in tissue repair and tissue homeostasis. In the last decade, the neutrophil field has suddenly won a new dynamic with new remarkable findings that came to shake all the preexistent knowledge about their lifespan, life cycle, circadian and metabolic regulation, migration, heterogeneity, and fate. There is quite a good amount of knowledge regarding neutrophils and their function in homeostasis and in traditional inflammatory conditions. However, millions of people all around the world live with chronic low-grade systemic inflammation that can be triggered by different environmental or genetic factors. In our lab, we focus on understanding how neutrophils and the neutrophilic "traditional" inflammatory response to injury are altered by the presence of systemic inflammation, with a particular focus on metainflammation (inflammation triggered by metabolic imbalance) and inflammaging (inflammation triggered by aging). In addition, we also study how neutrophils regulate the development and progression of liver diseases, including Non-alcoholic Fatty Liver Disease (NAFLD), Hepatocellular Carcinoma (HCC), and Fibrolamellar Carcinoma (FLC). We take advantage of the remarkable zebrafish animal model known for its optical transparency and ease of genetic and pharmacological manipulation to visualize and deconvolute the molecular mechanism involved in the neutrophil response in a whole-animal context. Currently, we have projects focused on:
1- Neutrophil in Polytrauma: Trauma is a major public health crisis worldwide, and the number one leading cause of death from age 1 to 46. Neutrophils play a crucial pathological role in the posttraumatic inflammatory response. Importantly, dysregulation of neutrophil responses and function due to pre-existent metabolic syndrome and associated metainflammation, contribute to increased susceptibility to develop posttraumatic complications in high-risk groups. Therefore, the goal of this project is to determine the mechanisms governing neutrophil responses in polytrauma in healthy and metainflammation conditions.
2- Impact of aging on neutrophils: Aging is a complex biological process that associates with altered systemic metabolism and a dampened immune response. Aging predisposes individuals to infections and sets the basis for the development of several age-related diseases including metabolic syndrome, type 2 diabetes, Alzheimer’s disease, and cancer. Distinct neutrophil populations have been linked to certain diseases and phenotypes. However, how aging contributes to neutrophil reprogramming and altered function, and if such a process affects overall heterogeneity contributing to the immune function decline remains completely unexplored. The goal of this project is to understand how aging impacts neutrophil biology and how can we revert age-associated decline in immune function and bolster immune response in older adults.
3- Neutrophils in liver disease: The role of immune cells in liver disease progression is unquestionable, and several immune cells have been implicated in the progression of NAFLD/NASH to liver cancer. However, the specific cellular and molecular immune mechanisms that regulate disease progression in vivo remain unclear, particularly the mechanisms involved in the crosstalk between innate and adaptive immune systems. In our lab, we have different projects focused on liver disease (NAFLD/NASH) and cancer (NASH-associated HCC, FLC, and HCC) to investigate the pathophysiological role neutrophils play in the progression of liver diseases and to unravel neutrophil-dependent mechanisms that regulate liver immune landscape.
The Zebrafish Model
In our lab, we use the Zebrafish model, a well-established vertebrate system known for its exceptional transparency and scalability that provides us with an unprecedented opportunity to perform large-scale non-invasive live imaging of immune cell responses and to deconvolute the cell-cell interactions in a whole animal. We are taking advantage of this system to address fundamental questions on inflammaging and metainflammation and their relevance to the progression of human diseases by performing in vivo chemical and genetic manipulation of cellular and molecular mechanisms and ultimately visualize the impact of such approaches thru non-invasive live imaging. Importantly, by using a whole-animal context approach on juvenile zebrafish, we are having into account the complex disease scenarios established in presence of both innate and adaptive immune systems. We hope that this approach helps us to better mimic human disease and advance the scientific knowledge regarding the impact of aging and diet on neutrophils and its relevance in the context of the progression of different human diseases, the effectiveness of therapeutic approaches, and disease outcomes.
Lab website: https://sites.google.com/view/sofia-de-oliveira-lab/home