The new discovery offers a new strategy against harmful inflammation

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Scripps Research scientists have discovered a protein in cells of the immune system (called neutrophils) that may be a target against harmful inflammation. An imaging technique called Stochastic Optical Reconstruction High-Resolution Microscopy (STORM, right image) shows that in resting neutrophils, the WASH protein complex (green) forms a molecular cluster complex with microfilaments called F-actin (red) and with granular cargo (blue). ) near the plasma membrane (picture on the left). In the absence of WASH, the actin nucleator Arp2/3 (right, pink) downregulates, facilitating the secretion of toxic granules (right, green), leading to systemic inflammation. Author: Scripps Research

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

In a study published on September 21, 2022, Communications of natureResearchers have shown that a multiprotein “molecular machine” called WASH has a powerful role in curbing the excessive inflammatory activity of neutrophils, immune cells that are important early responders to infections.

“Our results point to the possibility of future therapies targeting this WASH-regulated pathway to inhibit neutrophil inflammation retaining most of the antimicrobial efficacy of neutrophils,” says senior study author Sergio Katz, Ph.D., professor in the Scripps Research Department of Molecular Medicine.

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

Many of the antimicrobial molecules that neutrophils secrete through 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 diseases and types of tissue damage, including bacterial blood infection known as sepsis, arthritis, “reperfusion” cell injury after lack of oxygen, smoke inhalation lung damage, inflammatory bowel disease, some types of cancer and even atherosclerosis, which causes thickening of the arteries, leading to heart attacks and strokes. However, scientists still have a lot to learn about how this process of exocytosis works.

In the new study, Katz and his team shed light on the important role of WASH in neutrophil exocytosis. Neutrophils, when they encounter signs of infection or inflammation, usually respond initially by exocytosis releasing milder compounds inside “gelatinous granules”—capsule-like shells named after one of the enzymes they contain. A second type of exocytosis, caused secondarily and usually only by a more serious infection or inflammation, involves the release of “azurophilic granules,” so called because they are linked by a common blue stain.

Azuraphilic payloads are much more powerful and more likely to damage bystander cells. The team showed that WASH normally facilitates the initial reaction of gelatinase granules, which involves the release of compounds that help neutrophils adhere to and move across surfaces, such as walls of blood vessels. At the same time, WASH generally deters the release of toxic cargoes of azuraphil pellets.

In experiments, neutrophils without WASH released an excess of azurophil granules. Mice with these neutrophils had blood levels of toxic azuraphil molecules, which are normally found in cases of harmful systemic inflammation. The mortality of such mice in an experimental sepsis-like condition was more than three times higher than that of normal mice.

“WASH seems important molecular switch which controls the response of neutrophils to infection and inflammation by regulating the release of these two types of antimicrobial cargo, says Katz. – If WASH is not working, the result is likely to be excessive and chronic inflammation.

“In this study, using state-of-the-art cell biology techniques, we learned how neutrophils control their timely response through sequential exocytosis and identified a molecular system that acts as a gatekeeper to this process,” adds Katz.

Katz and his colleagues continue to study WASH and other molecules involved in neutrophil exocytosis with the goal of finding possible drug molecules that can silence excessive azurophil granules exocytosis— for the treatment of inflammatory diseases — without damage neutrophils‘ functions as a first responder immune system.

The first authors of the study were senior researcher Jennifer Johnson, Ph.D., and postdoctoral fellows Elsa Meneses-Salas, Ph.D., and Mahalakshmi Ramadas, Ph.D., all members of the Catz lab at the time of the study.


A Newly Identified Neutrophil Subset Is a Promising Therapeutic Target for Inflammatory Diseases


Additional information:
Jennifer L. Johnson et al. Differential dysregulation of a granule subset in WASH-deficient neutrophils leading to inflammation, Communications of nature (2022). DOI: 10.1038/s41467-022-33230-y

Citation: New Discovery Offers New Strategy Against Harmful Inflammation (2022, September 22) Retrieved September 22, 2022, from https://medicalxpress.com/news/2022-09-discovery-strategy-inflammation.html

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