Sofia de Oliveira, Ph.D.

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.

Selected Publications:

1. Michael C, Martinez-Navarro F, de Oliveira S. Analysis of Liver Microenvironment during Early Progression of Non-Alcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma in Zebrafish. Journal of visualized experiments: JoVE. 2021 April. doi: 10.3791/62457.
2. Martínez-Navarro FJ, Martínez-Morcillo FJ, de Oliveira S, Candel S, Cabas I, García-Ayala A, Martínez-Menchón T, Corbalán-Vélez R, Mesa-Del-Castillo P, Cayuela ML, Pérez-Oliva AB, García-Moreno D, Mulero V. Hydrogen peroxide in neutrophil inflammation: Lesson from the zebrafish. Dev Comp Immunol. 2019 Dec 17;105:103583. doi: 10.1016/j.dci.2019.103583. [Epub ahead of print] Review. PubMed PMID: 31862296.
3. de Oliveira S*, Houseright RA, Korte BJ and Huttenlocher A*. (2019) DNAJB1-PRKACA fusion induces liver inflammation in zebrafish model of Fibrolamellar Hepatocellular Carcinoma. pre-print form at BioRxiv https://doi.org/10.1101/781583
4. de Oliveira S*, Houseright RA, Graves AL, Golenberg N, Korte BG, Miskolci V, Huttenlocher A*. Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish. J Hepatol. 2019 Apr;70(4):710-721. doi: 10.1016/j.jhep.2018.11.034. Epub 2018 Dec 18. PubMed PMID: 30572006; PubMed Central PMCID: PMC6436385.
5. Kastenhuber ER, Craig J, Ramsey J, Sullivan KM, Sage J, de Oliveira S, Riehle KJ, Scott JD, Gordan JD, Bardeesy N, Abou-Alfa GK. Road map for fibrolamellar carcinoma: progress and goals of a diversified approach. J Hepatocell Carcinoma. 2019;6:41-48. doi: 10.2147/JHC.S194764. eCollection 2019. PubMed PMID: 30951568; PubMed Central PMCID: PMC6362920.
6. Gabellini C, Gómez-Abenza E, Ibáñez-Molero S, Tupone MG, Pérez-Oliva AB, de Oliveira S, Del Bufalo D, Mulero V. Interleukin 8 mediates bcl-xL-induced enhancement of human melanoma cell dissemination and angiogenesis in a zebrafish xenograft model. Int J Cancer. 2018 Feb 1;142(3):584-596. doi: 10.1002/ijc.31075. Epub 2017 Oct 12. PubMed PMID: 28949016.
7. de Oliveira S*, Rosowski EE*, Huttenlocher A. Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol. 2016 May 27;16(6):378-91. doi: 10.1038/nri.2016.49. Review. PubMed PMID: 27231052; PubMed Central PMCID: PMC5367630.
8. de Oliveira S, Lopez-Muñoz A, Martínez-Navarro FJ, Galindo-Villegas J, Mulero V, Calado Â. Cxcl8-l1 and Cxcl8-l2 are required in the zebrafish defense against Salmonella Typhimurium. Dev Comp Immunol. 2015 Mar;49(1):44-8. doi: 10.1016/j.dci.2014.11.004. Epub 2014 Nov 8. PubMed PMID: 25445910.
9. de Oliveira S, Boudinot P, Calado Â, Mulero V. Duox1-derived H2O2 modulates Cxcl8 expression and neutrophil recruitment via JNK/c-JUN/AP-1 signaling and chromatin modifications. J Immunol. 2015 Feb 15;194(4):1523-33. doi: 10.4049/jimmunol.1402386. Epub 2015 Jan 12. PubMed PMID: 25582859.
10. de Oliveira S, López-Muñoz A, Candel S, Pelegrín P, Calado Â, Mulero V. ATP modulates acute inflammation in vivo through dual oxidase 1-derived H2O2 production and NF-κB activation. J Immunol. 2014 Jun 15;192(12):5710-9. doi: 10.4049/jimmunol.1302902. Epub 2014 May 19. PubMed PMID: 24842759.
11. Candel S*, de Oliveira S*, López-Muñoz A, García-Moreno D, Espín-Palazón R, Tyrkalska SD, Cayuela ML, Renshaw SA, Corbalán-Vélez R, Vidal-Abarca I, Tsai HJ, Meseguer J, Sepulcre MP, Mulero V. Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation. PLoS Biol. 2014 May;12(5):e1001855. doi: 10.1371/journal.pbio.1001855. eCollection 2014 May. PubMed PMID: 24802997; PubMed Central PMCID: PMC4011677.
12. de Oliveira S, Reyes-Aldasoro CC, Candel S, Renshaw SA, Mulero V, Calado A. Cxcl8 (IL-8) mediates neutrophil recruitment and behavior in the zebrafish inflammatory response. J Immunol. 2013 Apr 15;190(8):4349-59. doi: 10.4049/jimmunol.1203266. Epub 2013 Mar 18. PubMed PMID: 23509368; PubMed Central PMCID: PMC3736093.
13. Galindo-Villegas J, García-Moreno D, de Oliveira S, Meseguer J, Mulero V. Regulation of immunity and disease resistance by commensal microbes and chromatin modifications during zebrafish development. Proc Natl Acad Sci U S A. 2012 Sep 25;109(39):E2605-14. doi: 10.1073/pnas.1209920109. Epub 2012 Sep 4. PubMed PMID: 22949679; PubMed Central PMCID: PMC3465450.

*co-first authors or co-corresponding authors

A complete list of my published work is available in My Bibliography: 

https://www.ncbi.nlm.nih.gov/myncbi/1tyNtgESwTO5a/bibliography/public/