Neutrophils in the Immune System Do More Than Fight Bacteria and Viruses

Neutrophils are the most abundant immune cells in the human body and now, scientists are realizing, perhaps also among the least understood.

Neutrophils are a type of white blood cell that acts as a first responder when bacteria or viruses invade the body and cause infection. But their capabilities go far beyond what has been commonly known, according to Michael H. Nathanson, MD, PhD, Gladys Phillips Crofoot professor of medicine (digestive diseases), professor of cell biology at Yale School of Medicine (YSM), and co-director of the Yale Liver Center.

“People generally looked at neutrophils as bad cops rather than good cops—they just come in, they kill bacteria, they release all kinds of injurious agents that damage all the surrounding tissue, and then [other cells] come in and clean things up,” says Nathanson. “What we found is that neutrophils are also capable of doing something much more specific and less damaging.”

For years, Nathanson has been studying the importance of calcium signaling in liver cells. This signaling plays an essential role in regulating cell proliferation and bile secretion. Now, Nathanson and his team have discovered that neutrophils can influence calcium signaling in liver cells from patients with alcoholic hepatitis, a type of liver disease that results from excessive alcohol consumption. They published their study in the Journal of Clinical Investigation on June 25.

Nathanson and his team found that neutrophils release vesicles (sacs) filled with a protein called elastase into liver cells known as hepatocytes. The elastase breaks down proteins called ITPR2, which play a major role in regulating calcium levels.

In response to the neutrophils, the hepatocytes release proteins called Serpin E2 and A3, which degrade the elastase. This suggests that the neutrophils’ action is temporary, reversible, and nondestructive, which challenges the prevailing notion that neutrophils cause permanent damage to injured tissues.

“[The neutrophils] are able to dock with hepatocytes, transfer specific enzymes into the hepatocytes that transiently degrade certain proteins in the hepatocyte, and then the neutrophil goes on its merry way. The hepatocyte completely recovers as if nothing ever happened to it,” Nathanson says. “It’s a completely unexpected role for neutrophils.”

Nathanson and his team initially performed in vivo cell culture experiments to determine the mechanism of the neutrophils’ newly discovered role, and they corroborated the results in alcoholic hepatitis-induced mouse models. But what was particularly striking was that they also found evidence of that action by the neutrophils in human samples.

“In actual biopsies from patients with alcohol-associated hepatitis, we found that the neutrophil elastase was within the hepatocytes, so we’re pretty confident that this is actually what’s happening in patients,” Nathanson says.

When neutrophils insert elastase into hepatocytes, they break down the proteins needed for cell proliferation and bile secretion. But the researchers aren’t entirely sure why the neutrophils do this, or what the impact is for the course of a patient’s disease.

“Why is the neutrophil telling the hepatocyte to stop putting effort into proliferation and secretion and things like that? We’re not entirely sure,” Nathanson says. “In time, we need to understand why neutrophils are doing this and whether it’s helpful or damaging to the liver in the long run.”

There are few treatment options for alcoholic hepatitis, a severe and potentially life-threatening complication of alcohol-associated liver disease with a short-term mortality ranging from 20% to 50%. Steroids are the only treatment with a proven benefit, but the drugs don’t work for everyone with the disease. Nathanson hopes that understanding neutrophils’ new role could one day help inform new treatment options.

“If neutrophils are actually playing a beneficial role, then one might imagine trying to find a more targeted therapy that doesn’t interfere with their action,” Nathanson says.

Interestingly, Nathanson’s team also incubated neutrophils with other types of cells from lung, colon, and pancreatic human cell lines. The researchers found that the neutrophils exhibited the same effect on these other cell types, reducing calcium regulation through ITPR2 degradation. A next step will be to determine how the effects of neutrophils expressed in livers affected by alcoholic hepatitis differ from those involved in other forms of liver disease and those found in the bloodstream.

“Neutrophils are playing a completely unexpected and potentially beneficial role in different tissues under different circumstances,” Nathanson says. “We need to understand when this neutrophil phenotype is expressed—and in what diseases and in what tissues? And is it doing something good or bad? Is it something we want to promote or inhibit?”

Nathanson is excited by this new knowledge about neutrophils.

“We’re suddenly discovering that the most important immune cell is doing something completely different from what we thought it was doing,” he says. “So how could it not be important to understand why it’s doing that?”