The research team found that a multiprotein "molecular machine" called Wash restrains the excessive inflammatory activity caused by neutrophils while still preserving neutrophils' antimicrobial effectiveness (Nature Communications, September 21, 2022).

Neutrophils comprise about two-thirds of the white blood cells that circulate through human bloodstreams and the molecules neutrophils release via exocytosis are potent enough to harm healthy cells. Excessive and/or chronic release of these molecules at least partly underlies sepsis, arthritis, smoke inhalation injury to the lungs, inflammatory bowel disease, some cancers, and even atherosclerosis.

When neutrophils encounter signs of infection or inflammation, they respond by releasing milder compounds within gelatinase granules. The second type of exocytosis triggered by more severe infection or inflammation releases azurophilic granules. These are the molecules more likely to damage bystander cells, the researchers found.

Wash normally facilitates the initial gelatinase granule response and releases compounds that help neutrophils adhere to and move around surfaces such as blood vessel walls. Also, Wash normally restrains the release of azurophilic granules cargoes. In neutrophils without Wash, excessive amounts of azurophilic granules were released, the scientists discovered.

Mice with these neutrophils had azurophilic blood levels akin to people with systemic inflammation. The mortality rate of these mice was more than triple that of normal mice when experiencing sepsis-like conditions.

The research team is continuing to study Wash and other molecules involved in neutrophil exocytosis and aims to find candidate drug molecules that can decrease excessive azurophilic granule exocytosis without impairing neutrophils' functions as immune first responders.

Inhibiting white blood cell enzyme reduces lung metastases in mice: study
Researchers at The Wistar Institute and Jubilant Therapeutics have found an enzyme in neutrophils that promotes tumor growth and metastasis, pointing...

Cardiac mouse model shows role white blood cells play in arrhythmia
Feeding mice a diet lacking in potassium induces ventricular tachycardia, a rapid heartbeat, enabling researchers to study how different white blood cell...

Machine learning helps scientists map the mammalian immune system
The use of advanced machine-learning software has led to the identification of hundreds of new genes that likely affect the working immune system, according...

What makes immunotherapies successful in one tumor but not in others?
Researchers have developed a new framework to uncover pathophysiological and molecular features that determine the effectiveness of immunotherapies. The...

Rare immune stem cells could lead to treatments for COVID-19, cancer
Rare stem cells that give rise to neutrophils in human bone marrow could offer a path to developing treatments for diseases that involve the white blood...