Our Research
How presence of metainflammation and inflammaging impact neutrophils and their response?
In the last decade, the neutrophil field has suddenly won a new dynamic with new remarkable findings that came to shake all the pre-existent knowledge about their lifespan, life cycle, circadian and metabolic regulation, migration, heterogeneity, and fate. Currently it is widely accepted that neutrophils live more than just a few hours after leaving the bone marrow . These cell undergo aging in circulation following circadian patterns and contrary to what was described previously, neutrophils exhibit metabolic plasticity and undergo metabolic adaptations and distinct regulations that are critical for their differentiation and function. Moreover, neutrophils present phenotypic heterogeneity and functional flexibility, and recently it has been shown how their response during acute inflammation is regulated by distinct transcriptional networks. At chemotaxis level, with the development of new imaging techniques and new models visualization of neutrophil migration and behavior became easier and it was possible to show that neutrophils form swarms to control injury damage and pathogen dissemination, and that they can actually reverse migrate leavening the injury site or undergo NETosis (a form of cell death that involves the release of decondensed chromatin and granule components).
Obesity, metabolic syndrome and aging have been linked with dysfunctional immune response with leads to increased susceptibility to infections and wound healing defects. In addition, a dysfunctional and impaired immune response also contributes for the development of severe inflammatory complications with poor clinical outcome, as observed in COVID19 pandemic. In our lab we are investigating how the presence of chronic systemic inflammation and metabolic dysregulation triggered by the consumption of western diet or aging impact neutrophils and contributes to a dysfunctional inflammatory response. We are particularly interested in addressing the effect in the inflammatory process towards tissue damage and infection. With neutrophils emerging as powerful therapeutic targets, our findings will create new knowledge that will allow novel genetic and pharmacological approaches to improve neutrophil function and reduce the risk to develop serious complications and poor clinical outcomes from infections in the elderly and in individuals with metabolic syndrome and associated comorbidities and revert the ill-effects of aging and calorie rich diets consumption . Want to know more??? Go and check this Zebrafish Webinar!! Talk starts @ 1h40min of the video https://youtu.be/fQHNW7pDSqs
Whole-larvae Fluorescent Confocal Microscopy of Diet-induced Systemic Inflammation
Non-invasive Fluorescent Confocal Live Imaging of Innate Immune Cell Response
How do neutrophils regulate liver disease progression?
Non-Alcoholic Fatty Liver Disease/ Non-Alcoholic Steatohepatitis/ Hepatocellular Carcinoma
More than twenty five percent of the American citizens suffer from nonalcoholic fatty liver disease (NAFLD), the number one cause for aggravated liver disease and the necessity of liver transplantation. Consumption of western-type diets (High-sugar/high-fat/ high cholesterol) induce fat accumulation in hepatocytes, causing lipotoxicity, and liver damage which triggers inflammation and leads to the development of nonalcoholic steatohepatitis (NASH), a severe inflammatory form of NAFLD. NAFLD/NASH can progress to liver cancer, such as Hepatocellular Carcinoma (HCC). Several immune cells have been implicated in the progression of NAFLD/NASH to liver cancer, including neutrophils, macrophages/kupffer cells and T-cells. 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 use the zebrafish model, a well-established vertebrate system, which is amenable to large-scale non-invasive live imaging of immune responses and cell-cell interactions in a whole animal context. We are currently investigating how neutrophils and neutrophil derived components contribute to development and progression of NAFLD/NASH-HCC and how do they crosstalk with T cells at the liver.
Non-invasive Fluorescent Confocal Microscopy of Liver Microenvironment of NASH-associated HCC
de Oliveira, S et al; J Hepatology 2019
Neutrophil migration inside a liver of a larvae with NASH
Neutrophil undergoing NETosis in the liver of a larvae with NASH
Fibrolamellar Hepatocellular Carcinoma
In addition to the NAFLD/NASH-HCC zebrafish model , we have also developed a model for a rare type of liver cancer that affects children and young adults named Fibrolamellar Hepatocellular Carcinoma (FLC). New and interesting data from our lab and others suggest that inflammation is involved in the progression of FLC. We are deeply committed to continue our efforts to unravel the immune mechanisms involved in the pathophysiology of FLC, and will keep using our zebrafish models to study this ultra rare type of liver cancer. Currently we are focused in the role of inflammation in FLC. In addition, we are performing a pilot study to develop zebrafish “Avatars” to understand the biology of a rare type of liver cancer, the Fibrolamellar Carcinoma. We will be using these models to better characterize each patient tumor and to investigate the differences among FLC patients. This pilot study will be the foundation for future projects where we plan to use zebrafish xenograft models of liver cancers to evaluate the impact of diet on different therapeutic approaches and cancer progression. We are very fortunate to have the support of Cancer Research Institute and Fibrolamellar Cancer Foundation to continue our mission.
de Oliveira, S. DMM 2020