Our Research

How presence of systemic chronic inflammation impact neutrophils and their response?

Neutrophils, the most abundant leukocytes in circulation, are essential for immune defense, inflammation, and tissue homeostasis. Over the past decade, major discoveries have reshaped our understanding of their lifespan, metabolic regulation, heterogeneity, and fate.

Despite advances in neutrophil biology, millions suffer from chronic low-grade systemic inflammation, driven by metabolic dysfunction, aging, and environmental factors. Our uses complex models of inflammation to investigate how systemic inflammation impacts neutrophil biology and their role in disease (e.g., injury, infection, cancer), inflammatory cascade, and tissue regeneration. We are particularly interested in chronic systemic inflammation models of metainflammation (inflammation from metabolic imbalance), inflammaging (aging-associated inflammation), and chronic skin inflammation (e.g., psoriasis).

Want to know more??? Go and check this Zebrafish Webinar!! Talk starts @ 1h40min of the video https://youtu.be/fQHNW7pDSqs

Establishing a Zebrafish Model for Diet-Induced Metabolic Syndrome

To bridge the gap in dietary models for systemic inflammation, my lab, in collaboration with Sparos, developed standardized Western-type diets for zebrafish. I spearheaded a multi-laboratory consortium integrating expertise across lipid biochemistry (Steven Farber Lab, Carnegie Institution for Science), metabolic rewiring (John Rawls Lab, Duke), vascular calcification (Anabela Bensimon-Brito Lab, CBI Toulose), and liver immunopathology (de Oliveira Lab, Einstein). This effort has provided a comprehensive platform for dissecting diet-induced inflammation and metabolic dysfunction.

Overall, through cutting-edge imaging, the development of complex models of inflammation, and interdisciplinary collaborations, our lab remains at the forefront of neutrophil research. Our overarching goal is to expand our knowledge of neutrophil biology in disease and identify novel inflammation and tissue regeneration regulators.

Neutrophils in Single and Polytraumatic Injury

(supported by NIH/NIGMS, MIRA R35GM147416 and supplement NIH/NIGMS, MIRA R35GM147416, PI de Oliveira S)

Neutrophils orchestrate the early inflammatory response in trauma. Using our diet-induced metabolic syndrome model we visualized and investigated how under metainflammation neutrophil production, function, and behavior are drastically exacerbated and dysfunctional in vivo in a steady state and upon injury. Importantly, we found that neutrophils from inflamed regions such as the liver and intestine are a major source of activated and reprogramed neutrophils that fuel the dysfunctional neutrophilic inflammatory response to injury sites. Additionally, our lab uncovered that, in polytrauma, neutrophils prioritize vital organs (e.g., liver and spinal cord) over peripheral wounds (e.g., skin epithelium). A mechanism that breaks down in metainflammation, leading to increased mortality. We are expanding on these findings investigating: 1) mechanisms driving neutrophil injury prioritization in polytrauma versus single wounds; 2) impact of prioritization on injury outcome - survival, tissue regeneration and repair; 3) clarifying how metainflammation disrupts these responses.

Short-term high cholesterol diet induces Systemic Chronic Inflammation in zebrafish two week-old larvaeRepresentative maximum intensity projections of 14dpf Tg(lyzC:h2bmcherry/mpeg1;h2b-GFP) zebrafish larvae fed for 8 days with normal and high-cholesterol diets. Images were acquired on a spinning disk confocal microscope (CSU-X; Yokogawa) with a confocal scanhead on a Zeiss Observer Z.1 inverted microscope equipped with a Photometrics Evolve EMCCD camera using a NA 0.5/20x air objective, z-stacks, 5μm optical sections and 512x512 resolution, 8x1 tile images per larvae were taken, larvae mounted on a zWEDGI device. Acquisitions made by Sofia de Oliveira.

Whole-larvae Fluorescent Confocal Microscopy of Diet-induced Systemic Inflammation

Whole larvae imaging of neutrophilsWhole -larvae time-lapse movie of neutrophil recruitment to a tail-fin wound in 14dpf Tg(lyzC:h2bmcherry) zebrafish larvae fed for 8 days with high-cholesterol diet. Images were acquired on a spinning disk confocal microscope (CSU-X; Yokogawa) with a confocal scanhead on a Zeiss Observer Z.1 inverted microscope equipped with a Photometrics Evolve EMCCD camera using a NA 0.5/20x air objective, z-stacks, 5μm optical sections and 512x512 resolution, 8x1 tile images per larvae were taken every 5 minutes from 20 min post wounding until up to 24 hours after wounding, larvae mounted on a zWEDGI device . Acquisitions made by Sofia de Oliveira.

Non-invasive Fluorescent Confocal Live Imaging of Innate Immune Cell Response

High cholesterol diet primes neutrophils and leads to exacerbated response towards tail-fin woundTime-lapse movies of neutrophil and macrophage recruitment to a tail-fin wound in 14dpf Tg(lyzC:h2bmcherry/mpeg1;h2b-GFP) zebrafish larvae fed for 8 days with normal and high-cholesterol diets. Images were acquired on a spinning disk confocal microscope (CSU-X; Yokogawa) with a confocal scanhead on a Zeiss Observer Z.1 inverted microscope equipped with a Photometrics Evolve EMCCD camera using a NA 0.5/20x air objective, z-stacks, 5μm optical sections and 512x512 resolution, images were taken every 2 minutes from 20 min post wounding until up to 24 hours after wounding, larvae mounted on a zWEDGI device. Acquisitions made by Sofia de Oliveira. Neutrophils (yellow); Macrophages (magenta);

Non-invasive Intravital Imaging of Neutrophil Response to Polytraumatic

Advancing Neutrophil Behavior Analysis

Our lab pioneers quantitative neutrophil behavior profiling in the zebrafish model, which allows visualization and tracking of neutrophils by long-term, non-invasive intravital microscopy for over 16 hours. Using this unique approach, we plan to expand the work performed in mouse models to define distinct phenotypic behavior signatures across injury (single trauma versus polytrauma), infection, and cancer. We are using computational modeling, multi-omics, and genetic and pharmacological approaches to modulate neutrophil function in our disease inflammation models. Our goal is to use neutrophil behavior profiling to find druggable molecular targets to promote the enrichment (or eradication) of specific phenotypic behavior signatures associated with distinct functions (pro-resolution and regeneration; anti-tumor, anti-fibrotic, etc). Collaboration with Andres Hidalgo (Yale).

Inflammaging & Neutrophil Dysfunction

(supported by P&F Award from Einstein’s Nathan Shock Center in the Basic Biology of Aging – PI, de Oliveira S)

Aging alters neutrophil metabolism and immune function, increasing susceptibility to infections, malignancies, and chronic diseases. Our work focuses on 1) DDX41 germline mutations and their role in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) (collaboration w/ Bowman’s Lab); 2) The pro-inflammatory cytokine GDF15, its link to aging, and its effects on neutrophil function in MAFLD. Using mutagenesis, single-cell transcriptomic profiling, metabolic profiling, xenotransplantation, and live-imaging, we aim to define how aging reprograms neutrophil heterogeneity and function. Collaboration with Teresa Bowman Lab (Einstein)

Neutrophils in Liver Disease and Cancer

(supported by P&F Award from Marion Bessin Liver Research Center – PI de Oliveira S; Andrew McDonough B+ Foundation – PI de Oliveira S)

Neutrophils are pivotal in liver disease and cancer progression, yet their pro-regenerative and anti-tumor roles remain fairly unexplored in this context, particularly under Metabolic-Associated Steatotic Liver Disease (MASLD). We are investigating: 1) Pro-resolution neutrophil subsets as therapeutic targets for MAFLD; 2) Mechanisms to induce cytotoxic neutrophil populations with anti-tumor activity in HCC and FLC. By integrating intravital imaging, photoconversion tracking, proteomics, xenotransplantation, and transcriptomics, we seek to identify functional neutrophil states with therapeutic potential in liver disease. Collaboration with Yvonne Sanger Lab (Montefiore Einstein)

Non-invasive Intravital Microscopy of Liver Microenvironment of MASLD-associated HCC

High Cholesterol diet induces infiltration of innate immune cells to liver area Time-lapse movies of 13dpf Tg(fabp10a:ptBcatenin_cryaa:venus)/mfap4:tomato-caax/lyzc:bfp) larvae fed for 7 days with different diets. Images were acquired on a spinning disk confocal microscope (CSU-X; Yokogawa) with a confocal scanhead on a Zeiss Observer Z.1 inverted microscope equipped with a Photometrics Evolve EMCCD camera using a NA 0.5/20x air objective, z-stacks, 5μm optical sections and 512x512 resolution. Images were taken every 2 minutes, larvae mounted on a zWEDGI device. Neutrophils (yellow); Macrophages (magenta); Hepatocytes (green); Acquisitions made by Sofia de Oliveira
de Oliveira, S et al; J Hepatology 2019