Neutrophils are specialized white blood cells that act as first responders in innate immunity. But not much is known about the metabolic activity that powers them.
“Neutrophils, as important as they are, have not been widely studied in the metabolism field,” says Fan. “So this work fills an important knowledge gap.”
As the first line of immune defense, neutrophils need to activate quickly to recognize and react to infectious pathogens. Billions of these cells are produced in the bone marrow each day, so the cells are plentiful, but also short-lived.
“We kind of thought about it in a different way—because they’re so short-lived, it probably means they had to change their metabolism really quickly,” says graduate student Emily Britt, who was the first author on the study. “So we thought it would be worth pursuing, and then we saw these really big changes.”
When neutrophils are activated, they undergo an “oxidative burst” where they convert oxygen into a toxic form that can damage pathogens—a process that is metabolically expensive.
To learn more about this process, the research team tracked the metabolic pathways responsible for fueling oxidative burst by using isotopically labeled glucose.
“We saw that there were really cool shifts in the flow through these metabolic networks,” Britt says.
They found that the oxidative burst was being powered by a dynamic shift from metabolizing glucose through glycolysis to using the pentose phosphate pathway. And not only was glucose diverted to the pentose phosphate pathway, but some steps of glycolysis were reversed so that the glucose molecules could be recycled to pass through again.
This unique “pentose cycle” helps power the neutrophil to quickly turn on and attack pathogens at the immunological front line.
“As we saw those core changes, then next question was if we mess up those changes, are the cells still able to perform their functions?” says Britt.
Indeed, when the team experimentally blocked the pathway, there was no longer an oxidative burst, and the neutrophils lost the ability to kill pathogens.
With these dynamic and flexible changes, Britt and Fan note that this is just the first step in their investigation of neutrophil metabolism. They hope to dive deeper into other changes that they observed in this study.
“That’s the beauty of having an unbiased approach to discovery,” says Fan. “There’s many lines to follow up where we can go really deep and look into all these hints.”
In addition to neutrophil metabolism being a relatively new field, Fan notes that her lab wouldn’t have pursued this research without Britt’s initiative.
“It’s pretty brave to start on something pretty new and exciting,” Fan adds. “Everything is a mix of fun and challenges. We’re seeing that anything is possible!”