Scripps Research discovery suggests new strategy

image: Scripps Research scientists have discovered a protein in immune cells (called neutrophils) that may be a target for harmful inflammation. An imaging technique called super-resolution stochastic optical reconstruction microscopy (STORM, right image) shows that in resting neutrophils, the WASH protein complex (green) forms a clustered molecular complex with microfilaments called F-actin (red) and with granule cargo (blue) near the plasma membrane (left image). In the absence of WASH, the actin nucleator Arp2/3 (right, pink) has reduced activity, facilitating the secretion of toxic granules (right, green), leading to systemic inflammation.
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Credit: Scripps Research

LA JOLLA, Calif.—A team led by Scripps Research scientists has uncovered key 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 heart disease.

In the study, published on September 21, 2022 in Nature Communicationresearchers have shown that a multi-protein ‘molecular machine’ called WASH plays a powerful role in limiting the excessive inflammatory activity of neutrophils, immune cells that are important early responders against infections.

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

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

Many antimicrobial molecules that neutrophils release by exocytosis are potent enough to harm healthy cells. There is evidence that excessive and/or chronic release of these molecules underlies at least in part serious medical conditions and types of tissue damage, including the bacterial blood infection condition known as sepsis. , arthritis, “reperfusion” damage to cells after oxygen deprivation, smoke inhalation lung damage, inflammatory bowel disease, some cancers and even atherosclerosis which thickens the arteries and leads to heart attacks and strokes. stroke. Yet scientists still have a lot to learn about how this exocytosis process works.

In the new study, Catz and his team shed light on the important role that WASH plays in neutrophil exocytosis. Neutrophils, when encountering signs of infection or inflammation, typically respond initially by releasing, through exocytosis, milder compounds into “gelatinase granules” – capsule-shaped enclosures named after the one of the enzymes found there. A second type of exocytosis, triggered secondarily and usually only by more severe infection or inflammation, involves the release of “azurophilic granules”, so called because they are bound by a common blue spot. Azurophile cargoes are much more potent and are more likely to damage neighboring cells. The team showed that WASH normally facilitates the initial gelatinase granule response, which includes the release of compounds that help neutrophils adhere to and move around surfaces such as blood vessel walls. At the same time, WASH normally limits the release of toxic azurophile granule cargoes.

In experiments, neutrophils without WASH released excessive amounts of azurophil granules. Mice with these neutrophils had blood levels of toxic azurophile molecules normally found in cases of harmful systemic inflammation. The mortality rate of these mice during an experimental sepsis-like state 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,” Catz says. “When 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 revealed how neutrophils control their rapid response through sequential exocytosis and identified a molecular system that acts as the gatekeeper for this process,” adds Catz.

Catz and colleagues continue to study WASH and other molecules implicated in neutrophil exocytosis, with the goal of finding candidate molecules capable of mitigating excessive azurophil granule exocytosis – to treat inflammatory conditions – without altering the functions of neutrophils as immune first responders.

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

“Differential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes leading to inflammation” was co-authored by Jennifer Johnson, Elsa Meneses-Salas, Mahalakshmi Ramadass, Jlenia Monfregola, Farhana Rahman, Raquel Carvalho Gontijo, Kersi Pestonjamasp , Dale Allen, Jinzhong Zhang, Kasra Askari, Danni Chen, Juan Yu, Scott Henderson, Nathan Wineinger, and Sergio Catz of Scripps Research; William Kiosses, Yanfang Peipei Zhu and Catherine Hedrick of the La Jolla Institute of Immunology; Douglas Osborne and Daniel Billadeau of the Mayo Clinic; Matilde Valeria Ursini of the Institute of Genetics and Biophysics of the Italian National Research Council A. Buzzati Traverso; and Sergio Grinstein from the University of Toronto.

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

About Scripps Research

Scripps Research is an independent, nonprofit biomedical institute ranked the world’s most influential for impact on innovation by the Nature Index. We advance human health through profound discoveries that address pressing medical concerns around the world. Our drug discovery and development division, Calibr, works hand-in-hand with scientists from all disciplines to bring new drugs to patients as quickly and efficiently as possible, while teams at the Scripps Research Translational Institute harness genomics , digital medicine and advanced computing to understand individual health and make healthcare more efficient. Scripps Research also trains the next generation of top scientists at our Skaggs Graduate School, consistently named one of America’s Top 10 Chemistry and Biological Sciences programs. Learn more at www.scripps.edu.


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