Novel Strategy Against Harmful Inflammation: Scientists Identify WASH Protein Complex as Gatekeeper of Neutrophil-Induced Inflammation – News Azi

In the study published September 21, 2022 in nature communicationthe researchers showed that a multiprotein ‘molecular machine’ called WASH plays an important role in curbing excessive inflammatory activity of neutrophils, immune cells that are key early responders to infection.

“Our results indicate the possibility of future treatments that target this WASH-regulated pathway to inhibit neutrophil-related inflammation while preserving most of the neutrophil’s antimicrobial efficacy,” says Sergio Catz, senior author of the study, PhD, professor in the Department of Molecular Medicine at Scripps Research.

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

Many of the antimicrobial molecules that neutrophils release through exocytosis are powerful enough to damage healthy cells. There is evidence that excessive and/or chronic release of these molecules underlies, at least in part, serious diseases and types of tissue injury, including the bacterial blood infection known as sepsis, arthritis, “reperfusion” damage to cells following oxygen starvation, smoking, and inhalation injuries lungs, inflammatory bowel disease, some cancers, and even the artery-thickening atherosclerosis that leads to heart attacks and strokes. However, scientists still have a lot to learn about how this process of exocytosis works.

In the new study, Catz and his team shed light on the important role that WASH plays in neutrophil exocytosis. Typically, when neutrophils encounter signs of infection or inflammation, they first respond by exocytizing to release milder compounds into “gelatinase granules” — capsule-like shells named for one of the enzymes they contain. A second type of exocytosis, which is secondary and usually only triggered by more severe infection or inflammation, involves the release of “azurophilic granules,” so named because they’re bound by a common bruise. Azurophilic charges are far more effective and more likely to damage surrounding cells. The team showed that WASH normally facilitates the initial gelatinase-granule reaction, which involves the release of compounds that help neutrophils attach to and move around in surfaces such as blood vessel walls. At the same time, WASH normally inhibits the release of toxic azurophilic granular charges.

In experiments, neutrophils without WASH released excessive amounts of azurophil granules. Mice with these neutrophils had blood levels of toxic azurophil molecules normally found in deleterious systemic inflammation. The mortality 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 controls neutrophil responses to infection and inflammation by regulating the release of these two types of antimicrobial cargo,” says Catz. “When WASH is dysfunctional, the result is likely excessive and chronic inflammation.”

“In this study, we used cutting-edge cell biology approaches to uncover how neutrophils control their timely response through sequential exocytosis, and identified a molecular system that acts as the gatekeeper of this process,” adds Catz.

Catz and his colleagues continue to study WASH and other molecules involved in neutrophil exocytosis with the goal of finding candidate drug molecules that can dampen excessive azurophil granule exocytosis – to treat inflammatory diseases – without compromising the functions of the Impairing neutrophils as first responders of the immune system.

The study’s co-first authors were senior staff scientist Jennifer Johnson, PhD, and postdoctoral researchers Elsa Meneses-Salas, PhD, and Mahalakshmi Ramadass, PhD, who were 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).