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 is 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). Currently, we have projects focused on:
1- How do diet and Age-related immunometabolic dysfunction impacts Neutrophils: Aging, obesity, and metabolic syndrome induce a systemic low grade of inflammation usually called inflammaging and metainflammation respectively. Such conditions drive dysfunctional immune responses that lead to auto-inflammatory diseases, chronic inflammatory conditions, and cancer. Neutrophils play a crucial role in the establishment of such chronic conditions. Neutrophil dysfunctional and hyperreactive response found in inflammaging and metainflammation scenarios has been linked to poor prognosis on life-threatening infections, including influenza and Sars-CoV-2. Excitingly, recent advances in the neutrophil field have identified novel subpopulations of these cells that exhibit functional heterogeneity. Additionally, metabolic and epigenomic reprogramming of neutrophils that occur during the trained immunity process, primes neutrophils for augmented functionality and hyperreactivity but also have the potential to alter dynamic transitions between subpopulations impacting host outcome and immune response. Distinct neutrophil populations have been linked to certain diseases and phenotypes. Our goal is to understand the mechanisms that mediate hyper-reactive immune system responses to “secondary” inflammatory triggers in the context of aging and metabolic syndrome. We are particularly interested in investigating the impact of such dysregulation on neutrophils' biology and address how such an effect modulates the inflammatory response towards tissue damage and infection. We plan to be able to identify molecular targets that mediate the hyper-responsiveness of neutrophils, which will allow us to revert the ill-effects of aging and calorie-rich diets on the immune system.
2- What is the role of neutrophil in development and progression of liver disease and cancer: 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. We are currently investigating the cell-specific role for inflammasome activation due to immune metabolic dysregulation in neutrophils and how it modulates T-cell infiltration, expansion, polarization, and fate in the liver. In addition, we are performing studies with zebrafish xenotransplants with the aim to better understand the impact of diet on immune cells and its impact on HCC and Fibrilamellar Carcinoma. We are also performing a pilot study to develop zebrafish “Avatars” to understand the biology of the rare type of liver cancer, Fibrolamellar Carcinoma. We will be using these models to better characterize each patient tumor and to investigate the differences among FLC patients. These studies will be the foundation for future projects where we plan to use zebrafish xenograft models of liver cancers (and other cancers) to evaluate the impact of diet on different therapeutic approaches and cancer progression.
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 its 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