According to a study published in Nature, a key step into how the immune system powers inflammation has been discovered by Klaus Ley, M.D., a scientist at the La Jolla Institute for Allergy & Immunology. Ley’s finding provides new insights into the vital biological mechanisms underlying cardiovascular disease and other disorders.

The study focused on neutrophils – important immune cells which play a vital role in many diseases. Dr. Ley, a pioneer in vascular immunology and head of the La Jolla Institute’s Division of Inflammation Biology, explained:

“Neutrophils are the body’s first line of defense and the main cell protecting us from bacterial infections. While their protective function is very positive, neutrophils also have inflammation-producing properties that cause problems in heart disease and a host of autoimmune diseases, for example lupus. This makes understanding how to manipulate these cells extremely important in disrupting disease.”

According to Shu Chien, M.D., Ph.D., a UC San Diego professor and director of UCSD’s Institute of Engineering in Medicine, Dr. Ley’s finding provides considerable new insights into inflammatory mechanisms in disease.

Dr. Chien said:

“They have elucidated the molecular and mechanical bases of this type of neutrophil rolling (in the blood vessels) that have major significance in inflammation. Since inflammation is at the root of a large variety of diseases, these findings not only have fundamental importance in the mechanobiology of the cell, but also in understanding the pathophysiology of many disease states.”

According to Dr. Ley, when blood flow is extremely fast, neutrophils attach on to the blood vessel wall using sling-like membrane tethers. In the study, Dr. Ley and Prithu Sundd, Ph.D., a researcher at La Jolla Institute, used a novel imaging technique they developed in 2010 in order to see and photograph the neutrophil adhesion process.

Over the years, Dr. Ley’s work has improved scientific understanding of the role of neutrophils in causing inflammation and his new finding provides another “major insight”, said Sussan Nourshargh, Ph.D., professor of Microvascular Pharmacology and head of the Center for Microvascular Research at Barts and The London Medical School, University of London.

Nourshargh highlights Dr. Ley’s finding of the leukocyte adhesion cascade – the process used by neutrophils to attach onto the blood vessel wall as they get ready to travel to infection sites. Dr. Ley’s new work shows another vital step in that process.

Nourshargh explained:

“This is a completely new cellular concept that will now be added as an additional step to the leukocyte adhesion cascade that describes the sequential cellular responses involved in guiding neutrophils to sites of inflammation. This pioneering work will without doubt pave the way for other researchers to explore the occurrence of “slings” in a wide range of inflammation scenarios.”

Neutrophils move around the body through the blood stream to fight infections, but in order to do this they must travel through the blood vessel walls of sites of inflammation, infection, or injury.

Dr. Ley and team focused on how neutrophils attach to the blood vessel wall, rather than their migration out of the blood vessel.

Dr. Ley said “This is important because it provides an opportunity to develop new treatments based on modulating or blocking one of the steps in the adhesion cascade.”

Results from previous studies have demonstrated that blocking just one of the steps can significantly reduce neutrophil recruitment.

Dr. Ley explained: “The cells separate their cytoskeleton from the cellular membrane, wrapping the sling around themselves like a lasso and then digging their hooks into the blood vessel wall.”

When there is a site of inflammation in the body, the blood flow increases because the blood transports immune cells to the site to promote healing. Although inflammation is a normal part of the healing process, in certain diseases it is undesired.

Dr. Ley said:

“For these cells, adhering under high shear is like being in a huge wind storm. The challenge in this storm is not to get blown away.

The body needs to have enough neutrophils to fight off bacteria faster than they can grow. Better understanding of neutrophil adhesion could be very beneficial in that process. Conversely, interrupting this process could have major impacts in autoimmune and other inflammatory diseases.”

Written by Grace Rattue