Deciphering Neutrophil Activity in the Presence of Trauma: A Scientist's Focus

Inflammation plays an important role in healing and recovery. As one of the first immune cells to respond to injury or infection, neutrophils play a critical role in the body's inflammatory response. 

Sofia de Oliveira, Ph.D., is focused on understanding the role of neutrophils in disease development and progression by studying the mechanisms that regulate their response to health and disease in the presence of systemic inflammation. Her lab is particularly interested in the role that neutrophils play in wounding and liver disease.

"We know that the presence of metabolic syndrome and associated systemic inflammation negatively affects the function of neutrophils, impairing their capacity to fight infections while simultaneously promoting tissue damage and exacerbating inflammation," says de Oliveira who is an assistant professor in the department of developmental & molecular biology and in the department of medicine (hepatology). "Now we want to know how and what the impact is in inflammatory response and disease progression."

The answer may come from studying zebrafish. They share approximately 75% of the same genes as humans and about 80% of genes associated with all human diseases, such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, and cancer.

Like in humans, when zebrafish were fed western diets it triggered the development of metabolic syndrome, leading to NAFLD and systemic chronic inflammation, which is responsible for neutrophil dysfunctional and hyperactive response to injuries as her lab has shown recently.

This is no small thing. The inability for neutrophils to help with healing is crucial to sustain a normal and effective immune response to trauma and infection and may even have played a part in the high number of deaths among many at-risk individuals during COVID who had metabolic syndrome and NAFLD.

Her latest research focus is on trauma. Traumatic injuries are a leading cause of death and disability in people between the ages of 1 and 46. Her lab has recently found that in a polytrauma scenario where zebrafish are challenged with concurrent injuries, neutrophils prioritize wounds in vital organs like the liver over tissues such as the skin. 

Prioritization hypotheses are not new in the neutrophil field but have mostly been studied in the context of wound versus infection. “We think that traumatic injuries in different tissues might also be sensed by neutrophils differently, using mechanisms that are lost in the presence of diet-induced systemic inflammation,” adds de Oliveira.

Now she and her research team are performing omic analysis and mechanistic studies to understand how neutrophils are impacted by the presence of diet-associated systemic chronic inflammation and liver disease in order to understand how such changes impact neutrophil response towards concurrent injuries and infection.

Dr. de Oliveira’s interest in neutrophils started at the beginning of her career at the Carlota Saldanha lab at the Institute of Molecular Medicine where she studied inflammation using murine models and ex vivo cells isolated from human blood. She quickly got hooked on neutrophils due to their amazing capacity to quickly respond to threats and regulate all the inflammatory processes. 

"Initially, we had many limitations in the field, such as the short lifespan after isolation from blood, lack of good cell culture models, and the need to use invasive methodologies in mice to visualize these cells in action," says de Oliveira. 

This inspired her to find a more suitable alternative and she found the zebrafish model, which was just emerging as a new system to study human diseases.

After that, she dedicated her Ph.D. work to help the field establish the zebrafish model as a system to study neutrophils and the mechanisms that regulate neutrophil recruitment to injury, infection, and chronic skin disease. 

"I always looked at neutrophils as the underdog of the immune cells," says de Oliveira. "On the surface, their role seems very perfunctory: they are activated and recruited very quickly, then fight and die."

According to de Oliveira, that’s not the full story. In fact, some neutrophils don’t die at all. They go from the injury site and migrate back into circulation, with an unknown purpose and using mechanisms that are still under study. Coincidentally, this process was discovered for the first time in the zebrafish model back in 2006 by de Oliveira's postdoc mentor Dr. Anna Huttenlocher. She says that neutrophils play way more roles than previously thought, not just in disease but under normal homeostasis.

The view of neutrophils has changed completely in the last few years with new and interesting findings about neutrophil biology emerging every month. 

Who else is interested in neutrophils? The National Institutes of Health, which recently awarded de Oliveira a $2.1 million grant to study them. 

Adds Oliveira, "We are living in an exciting era in the neutrophil field, and we plan to be part of this journey, pushing forward and contributing with great scientific achievements."