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Researchers publish the first blueprint of transcriptional factors that control neutrophil-driven inflammation in Nature Immunology.

Neutrophil surrounded by blood cells © Shutterstock

Neutrophils are important cells in the immune system, produced in very large numbers in the bone marrow. When in circulation they patrol blood vessels and tissues seeking out sources of disease or damage to regulate inflammatory and immune responses.

Evidence supports the idea that neutrophils are transcriptionally active cells that have the ability to adapt their genome and change the function of the cell en route to tissues. They display different functions such as phagocytosis, generating reactive oxygen species, and producing cytokines in response to inflammation. But the area remains largely unexplored.

Irina Udalova, Professor of Molecular Immunology at the Kennedy Institute for Rheumatology and senior author of a new study published in Nature Immunology said: "We know very little about neutrophil molecular wiring as it's an emerging field of study. So, our question was how the neutrophils change from the point of being developed in the bone marrow, then being released into the blood, and getting into the tissue. We discovered that rather than being static cells, they are remodelling their chromatin during their life cycle and that remodelling is often associated with transcriptional activity."

Having established that neutrophils do change during their transition to the tissue, the team then wanted to understand what transcriptional factors shape the responses.

Dr Tariq Khoyratty, lead author of the study, identified two transition points in neutrophil state, from bone marrow to the blood and from the blood to the tissue, each associated with the involvement of a distinct set of transcriptional factors. The co-lead author, DPhil student Zhichao Ai, then systematically deleted these in a model system of neutrophil development and examined the effect of deletions on neutrophil responses. By validating each factor in various functional assays, and then in in vivo models of inflammation, the team were able to build up the first transcriptional blueprint of neutrophil activity during inflammation.

"This is the first study that gives us a proof of principle that it might be possible to assign specific transcription factors to specific neutrophil states in chronic inflammatory disorders and therefore a step towards developing medical treatments in future. For example, stimulation of neutrophil maturation may be beneficial for post-chemotherapy cancer patients, whereas inhibition of neutrophil activation may help to reduce the inflammatory burden suffered during inflammation-associated diseases," said Irina.

The study was funded by Irina's Wellcome Trust Investigator Award entitled "Molecular control of pathogenic neutrophil responses in inflammation" and involved a collaboration with Andres Hidalgo's group at the Centro Nacional de Investigaciones Cardiovasculares Carlos III in Madrid.

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