An important step in the journey of inflammation-producing immune cells
has been discovered by scientists. The finding
provides powerful, previously unknown information about critical biological
mechanisms underlying heart disease and many other disorders.
The study, published today in Nature
focuses on one of the body's most abundant and important immune cells, known as
neutrophils, which play a pivotal role in many diseases. "Neutrophils are the
body's first line of defense and the main cell protecting us from bacterial
infections," said Dr. Ley, a pioneer in vascular immunology and head of the La
Jolla Institute's Division of Inflammation Biology. "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."
National Medal of Science winner Shu Chien, M.D.,
Ph.D., a UC San Diego professor renowned for his work on vascular mechanisms
and atherosclerosis, praised Dr. Ley's finding as a significant advance in
understanding inflammatory mechanisms in disease. "They have elucidated the
molecular and mechanical bases of this type of neutrophil rolling (in the blood
vessels) that have major significance in inflammation," said Dr. Chien,
director of UCSD's Institute of Engineering in Medicine. "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."
In his Nature
"'Slings' enable neutrophil rolling at high shear," Dr. Ley revealed
how neutrophils use sling-like membrane tethers to latch on to the blood vessel
wall during periods when blood flow is very fast. In making the discovery, Dr.
Ley and Prithu Sundd, Ph.D., a researcher at La Jolla Institute, used "dynamic
footprinting," a pioneering imaging technique they developed in 2010 that uses
special microscopes and total internal reflection microscopy to see and
photograph the neutrophil adhesion process with unprecedented clarity. Alex
Groisman, Ph.D., an associate professor in UCSD's Department of Physics, was
instrumental in developing and constructing the microfluidic device in which
these experiments were conducted and collaborated on the Nature paper.
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, said the work provides
another "major insight" from Dr. Ley whose discoveries, over the years, have
repeatedly enhanced scientific understanding of the role of neutrophils in
causing inflammation. In particular, she cited Dr. Ley's groundbreaking work on
the discovery of the leukocyte adhesion cascade, which explained the sequential
steps used by neutrophils to clamp onto the blood vessel wall as they prepare
to migrate to sites of infection. His latest finding reveals another important
step in that process.
"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," she said. "This pioneering work will without doubt pave
the way for other researchers to explore the occurrence of "slings" in a wide
range of inflammatory scenarios."
Like other immune cells, neutrophils travel throughout the body via the blood
stream pursuing their infection-fighting duties. In order to accomplish their
work, neutrophils must migrate through the blood vessel walls to sites of
infection, injury or inflammation.
"The activities of neutrophils are very important
for our survival, so they are the subject of significant scientific study,"
said Dr. Ley. While some scientists study their migration out of the blood
vessel, Dr. Ley's lab has focused on how neutrophils adhere to the blood vessel
wall. "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," said Dr. Ley, noting that earlier studies have shown that blocking
even one of the steps can severely reduce neutrophil recruitment.
While Dr. Ley has previously shown how
neutrophils adhere when blood flow is slow, his latest study reveals that
neutrophils use long membrane tethers at the front of the cell, termed
"slings," to slow down during high blood flow. The cells do this by
separating their cytoskeleton from the cellular membrane, wrapping the sling
around themselves like a lasso and then digging their hooks into the blood
vessel wall, said Dr. Ley. High blood flow occurs during inflammation, when the
body rushes immune cells to a site to promote healing. Inflammation is a normal
part of the healing process, but is unwanted in certain diseases.
"For these cells, adhering under high shear is
like being in a huge wind storm," said Dr. Ley. "The challenge in this storm is
not to get blown away."
Dr. Ley's studies could prove valuable in helping
scientists understand how to reduce adhesion, where inflammation is unwanted,
such as in heart or autoimmune disease, or to enhance the process, where more
neutrophils are desired, such as in bacterial infections like MRSA. "The body
needs to have enough neutrophils to fight off bacteria faster than they can
grow," he said. "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."