Neutrophil Plasticity in Infection and Inflammation

Neutrophils make up 40-60% of all white blood cells. They arrive as the first cell type wherever viral, bacterial, or fungal infections occur, or when tissue damage and injury happen. In severe and longer lasting incidents neutrophil numbers go up due to increased release from the bone marrow. Neutrophils detect, swallow up and destroy microbes, thereby acting as our immediate defense system. However, some microbes can evade neutrophils or sabotage their activities, leaving us less protected. Neutrophils are also part of healing processes after injury, but if prolonged and chronic conditions persist, their usually beneficial arsenal of chemicals, peptides and enzymes can lead to additional damage. Making toxic oxidants is a good example for this split between positive and negative outcomes of neutrophil activation. While essential for killing microbes, oxidants are also pro-inflammatory. Microbes have evolved ways to disable the oxidant-generating enzyme (called NOX2), however persistent oxidant release by neutrophils can lead to oxidative damage. In summary, neutrophils are essential for health but sometimes their actions need to be enhanced or downregulated. Lately, researchers recognized that neutrophils alter their genes (and proteins) depending on the environment that they encounter (‘neutrophil plasticity’). Certain locations, for example the lung and gut, or settings such as a particular microbial and pro-inflammatory milieu provoke comparable changes. Hence, neutrophil subtypes depend on the type of disease and its location and may provide a means to manipulate certain neutrophil functions with drugs. We discovered recently such new neutrophil type, characterized by an additional oxidant-producing enzyme, in patients with inflammatory bowel disease and cystic fibrosis. Here we will extend these observations to additional patients with gut and lung diseases and will determine how this newly acquired enzyme alters disease outcomes. These insights will support developing treatments that can modify activated neutrophils in infectious and inflammatory disease.
 

Award Date
01 July 2022
Award Value
€369,881.00
Principal Investigator
Professor Ulla Kanus
Host Institution
University College Dublin
Scheme
ILP