New strategy against harmful inflammation: Scientists identify the WASH protein complex as a gatekeeper of neutrophil-driven inflammation

A team led by scientists at Scripps Research has uncovered important details of an immune cell process that often underlies excessive inflammation in the body. The findings could lead to new ways to prevent and/or treat inflammation-related conditions such as sepsis, arthritis and coronary artery disease.

In the study, published September 21, 2022 in nature communicationthe researchers showed that a multi-protein “molecular machine” called WASH plays a powerful role in counteracting excessive inflammatory activity by neutrophils, immune cells that are important early responders to infection.

“Our findings point to the possibility of future treatments targeting this WASH-regulated pathway to inhibit neutrophil-driven inflammation while preserving most of the antimicrobial effectiveness of neutrophils,” said senior author Sergio Catz, PhD, professor in the department. Molecular Medicine at Scripps Research.

Neutrophils are workhorses of the mammalian immune system and comprise about two-thirds of the white blood cells that circulate through our bloodstreams. They fight invading microbes by engulfing and digesting them, and by releasing a variety of antimicrobial molecules through a process called exocytosis.

Many of the antimicrobial molecules that neutrophils release via exocytosis are potent enough to damage healthy cells. There is some evidence that excessive and/or chronic release of these molecules is at least partially responsible for serious medical conditions and types of tissue damage, including the bacterial blood infection known as sepsis, arthritis, “reperfusion” damage to cells after oxygen deprivation, smoke inhalation damage to the lungs, inflammatory bowel disease, some cancers and even the artery-thickening atherosclerosis that leads to heart attacks and strokes. Still, scientists have much to learn about how this exocytosis process works.

In the new study, Catz and his team highlighted the important role WASH plays in neutrophil exocytosis. Neutrophils, when they encounter signs of infection or inflammation, usually respond initially by releasing, via exocytosis, milder compounds into “gelatinase beads” — capsule-like shells named for one of the enzymes found within. A second type of exocytosis, secondary and usually only caused by a more serious infection or inflammation, involves the release of “azurophilic granules,” so called because they are bound by a common blue spot. Azurophilic charges are much more powerful and more likely to damage bystander cells. The team showed that WASH normally facilitates the initial gelatinase granule response, which includes the release of compounds that help neutrophils attach to and move around surfaces such as blood vessel walls. At the same time, WASH normally limits the release of charges of toxic azurophilic granules.

In experiments, neutrophils without WASH released excessive amounts of azurophilic granules. Mice with these neutrophils had blood levels of toxic azurophilic molecules normally found in cases of harmful systemic inflammation. The death rate of such mice when experiencing an experimental sepsis-like condition was more than three times that of normal mice.

“WASH appears to be an important molecular switch that regulates neutrophil responses to infection and inflammation by regulating the release of these two types of antimicrobial cargoes,” Catz says. “If WASH is dysfunctional, the result is likely to be excessive and chronic inflammation.”

“In this study, using state-of-the-art cell biology approaches, we enjoyed how neutrophils control their timely response through sequential exocytosis, and identified a molecular system that acts as the gatekeeper of this process,” Catz added.

Catz and his colleagues continue to study WASH and other molecules involved in neutrophil exocytosis, with the goal of finding drug candidate molecules that can dampen excessive azurophilic granule exocytosis — to treat inflammatory conditions — without impairing the functions of neutrophils as the first immune response.

The study’s co-first authors were Senior Staff Scientist Jennifer Johnson, PhD, and postdoctoral researchers Elsa Meneses-Salas PhD, and Mahalakshmi Ramadass, PhD, all members of the Catz lab during the study.

The research was funded in part by the National Institutes of Health (P01HL152958, R01HL088256, R01AR070837, R01DK110162).

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