Researchers at Scripps Research identified WASH, a molecular machine that controls the excess neutrophil activity behind harmful inflammation. No drug targets WASH yet. But future drugs aimed at it would curb that damage without shutting down neutrophils outright. Shutting them down would lower immunity.
Inflammation is a defense reaction. But too much of it does more harm than good. It appears that neutrophils, the most common white blood cells, play a significant part in harmful inflammation. Yet shutting them down is not an option, because it would also lower immunity. Now researchers at Scripps Research have found a molecular machine called WASH. It plays a key role in keeping neutrophils from overreacting. Future drugs targeting WASH may help prevent harmful inflammation.
Inflammation is a defense reaction. It helps fight infections and helps tissue regrow. But too much inflammation, or inflammation out of control, does more harm than good. So excess inflammation causes arthritis, sepsis, and other health problems. And chronic, low-grade, uncontrolled inflammation causes coronary artery disease.
There are many drugs to control inflammation, but they have many drawbacks. Drugs like NSAIDs fail to help in many cases. For example, they might not help enough in arthritis. They may fail completely in sepsis or even low-grade chronic inflammation.
Corticosteroids are stronger anti-inflammatory drugs. But they suppress all kinds of inflammation and even immune activity. So long-term corticosteroid use does more harm than good. We need drugs that target only the bad inflammation. It seems that researchers at Scripps Research have found a way to do that. They now better understand harmful inflammation. They even found proteins that can lower it.
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In a study published in Nature Communications in September 2022, researchers from Scripps Research showed that a molecular machine made of many proteins, which they named WASH, can help suppress harmful inflammation by curbing excess neutrophil activity. Neutrophils are the most common white blood cells. So they play a key role in fighting infections and in inflammation. They can swallow germs and destroy them. To do this, they release chemicals through a process called exocytosis. The researchers found that neutrophils sometimes release far too many chemicals this way. That causes a lot of harm.
This neutrophil overreaction causes severe organ damage in conditions like body-wide infections. This faulty immune response adds to heart attacks and stroke, because it leads to atherosclerosis (hardened, clogged arteries). But shutting down neutrophils is not the way to fight bad inflammation, because it would also suppress immunity. So researchers set out to find the exact mechanism behind this overreaction.
In the new study, researchers at Scripps found that neutrophils respond to infection or inflammation in steps. First they release “gelatinase granules.” This first response is mild. It is good for fighting infections and helping tissue regrow. After that, they start a second, stronger response, most of all if the first one fails to beat the infection. This second response releases “azurophilic granules.” It appears that this second response causes much of the tissue damage.
But the body has its own way to hold back the azurophilic granule response. It uses the molecular machine WASH. That also means harmful inflammation happens because WASH activity runs low, which makes neutrophils misfire. So treatment for inflammation must target WASH, not neutrophils. These findings open the door to safer and more effective anti-inflammatory drugs. They would be good for both sudden and chronic inflammation. Drugs targeting WASH would not only help in arthritis. They may even help reduce the risk of health problems caused by chronic inflammation, like coronary artery disease.
For now, researchers have not found any drug that could control WASH. Still, it is a matter of time. So in the near future, we may see safer, more effective, and completely new kinds of anti-inflammatory drugs.
Frequently asked questions
Do neutrophils trigger inflammation?
Yes. Neutrophils are the most common white blood cells and the front line against infection. They swallow germs and destroy them by releasing chemicals through a process called exocytosis. Sometimes they release far too much, and that overflow damages the body’s own tissue. That excess is what turns a defensive reaction into harmful inflammation.
What causes neutrophilic inflammation to become harmful?
The Scripps team found neutrophils respond in two steps. First they release gelatinase granules. This mild response fights infection and helps tissue repair. If that fails, they step up and release azurophilic granules. That second wave causes most of the tissue damage. The molecular machine WASH normally holds the second wave in check. When WASH activity runs low, neutrophils misfire.
Why don’t NSAIDs or steroids fix harmful inflammation?
NSAIDs often fall short. They may not help enough in arthritis and can fail completely in sepsis or chronic low-grade inflammation. Corticosteroids are stronger. But they shut down all inflammation and immune activity alike, so long-term use does more harm than good. Neither targets only the bad inflammation. That is exactly the gap WASH could fill.
Is there a drug that targets WASH?
Not yet. Researchers have not found any drug that controls WASH activity. The finding moves the target. Treatment should aim at WASH, not at neutrophils themselves, because blocking neutrophils would weaken immunity. Drugs built that way could help in arthritis. They could also lower the risk of conditions driven by chronic inflammation, such as coronary artery disease.
Dr. Gurpreet Singh Padda, MD, MBA, MHP
