Novel Neutrophil-Derived Particle Is Potential Sepsis Biomarker

By Marilynn Larkin

December 16, 2020

NEW YORK (Reuters Health) - Newly identified particles, called elongated neutrophil-derived structures (ENDS), have been found in the blood of sepsis patients and may one day serve as a biomarker for early detection of the condition, researchers say.

"We have an IRB in place to collect longitudinal samples from septic patients. This prospective study will show whether ENDS numbers correlate with sepsis disease outcomes," Dr. Klaus Ley of the La Jolla Institute of Immunology told Reuters Health by email. With regard to the potential clinical impact, he said, "Much depends on the prospective study. It's too early to say."

Using advanced imaging technology, Dr. Ley and colleagues discovered by studying cells from mice and humans that neutrophils, as they move through the bloodstream, form tethers that get longer as the cells move along, eventually thinning out to about 150 nanometers and breaking off. Part of the tether stays with the neutrophil, while the broken fragment continues moving through the bloodstream, forming an ENDS, the researchers explain in their Journal of Experimental Medicine report.

ENDS do not contain mitochondria, endoplasmic reticulum, or DNA, but are enriched for 59 proteins, including the pro-inflammatory proteins S100A8, S100A9. "Within hours of formation, ENDS round up, and some of them begin to present phosphatidylserine on their surface (detected by annexin-5 binding) and release S100A8-S100A9 complex, a damage-associated molecular pattern protein that is a known biomarker of neutrophilic inflammation," they note.

In mice, ENDS appear in blood plasma upon induction of septic shock.

Compared with samples from healthy human donors, ENDS are 10-100-fold elevated in the blood plasma of septic patients.

Unlike neutrophil-derived extracellular vesicles, most ENDS do not contain the tetraspanins CD9, CD63, and CD81.

The authors state, "We conclude that ENDS are a new class of bloodborne submicron particles with a formation mechanism linked to neutrophil rolling on the vessel wall."

Dr. Andres Hidalgo of the Spanish National Center for Cardiovascular Research in Madrid, who was not involved in the study but is familiar with the team's work, elaborated in an email to Reuters Health. "In a snapshot, (this is) a new type of particle released by neutrophils as they bind the surface of inflamed vessels in a process known as rolling, because the cells literally 'roll' on the inside of blood vessels. The stickiness of the neutrophil and the production of elongated stretches from their membrane produce these particles when the membrane breaks. These structures, or ENDs, pack components of the original cell, including molecules typically associated with inflammation."

"Although the description of these ENDs and how they form is biologically elegant and beautiful, it is entirely unclear what their function may be in living organisms," he said. "Their elevated presence in septic patients may be used as a biomarker, but many other substances present in the blood during this type of inflammatory response" are also elevated.

Dr. Timothy Jones, Chief, Critical Care Medicine at Orlando Health and affiliated with Orlando Regional Medical Center in Florida, commented in an email to Reuters Health, "Currently, physicians can only use a broad assessment of clinical, laboratory, microbiologic, and radiographic data to determine if a patient is in sepsis. Oftentimes, that determination is slow. We have to give antibiotics first while we obtain more data over time."

"The discovery that ENDS are 10-100-fold higher in the blood plasma of patients with sepsis is very exciting," he said. "ENDS have the future potential of being a biomarker test day could shorten the time to proper diagnosis and limit the overuse of antibiotics."

SOURCE: Journal of Experimental Medicine, online December 4, 2020