When demand outpaces supply

Neutrophils are white blood cells that form the first line of defence against pathogens. They rush to the site, engulf and destroy the bacteria and fungi. These neutrophils, ironically, are also the reason behind increased morbidity from infection or injury in patients already suffering from a chronic inflammatory disorder such as obesity, Type 2 diabetes, cancer, or autoimmune conditions.

Researchers at the Indian Institute of Science (IISc) in Bengaluru have created a mouse model to demonstrate that, in patients with an inflammatory condition, immature neutrophils aggravate secondary infection (bit.ly/immature-neutrophils). "This negative role of immature neutrophils was suggested by researchers in the past, but there was no direct evidence," says Siddharth Jhunjhunwala, Associate Professor in the Department of Biotechnology. "We implanted a chitosan-based chip in the peritoneal cavity of a mouse, which triggered the release of neutrophils by up to 80 times more than normal," he says. The chip acted as the primary cause of inflammation. The mouse was given a secondary injury by injecting a lipopolysaccharide, causing acute lung injury. The team saw the inflammation had aggravated, and its condition was worse than that of the control mice not given the chitosan implant.

"We were able to prove that inflammation causes the release of immature neutrophils, and also that these immature neutrophils cause greater morbidity in a patient who gets a secondary infection or injury," says Jhunjhunwala. He points out that COVID-19 had shown that patients with pre-existing chronic inflammation conditions had worse outcomes than those without a co-morbidity, but scientists "didn't understand fully" why this was so. While the role of neutrophils was suspected, their mechanism remained unclear. Jhunjhunwala says that since neutrophils are sent to fight inflammation, in patients with chronic inflammation, the supply is unable to meet demand, so immature neutrophils are released from the bone marrow. And they create havoc.

The study also found that tweaking the functionality of immature neutrophils vastly improved the patient's condition. The drug molecule sivelestat, which inhibits human neutrophil elastase, an enzyme that destroys microbial proteins, showed promising results in improving the condition of the mouse. "We need to do a lot more work, like repeating the experiment with models having Type 2 diabetes," he adds.