To resolve inflammation, location matters

November 19, 2018 by Katherine Unger Baillie, University of Pennsylvania
Researchers from Penn and Technical University of Dresden found that the protein Del-1 takes on different functions depending on the cell that secretes it. When secreted by the immune system's macrophages, it acts as a bridge between those cells and neutrophils to help clear inflammation. Credit: University of Pennsylvania

Health conditions that involve inflammation run the gamut, from multiple sclerosis and lupus to arthritis, diabetes, and cancer. While inflammation can serve as a normal response to help the body deal with injury or infection, problems arise when it persists, potentially harming surrounding tissues.

To prevent or ameliorate this damage, the body relies on a strategy to actively clear inflammation. "It's not just extinguishing the fire of inflammation," says George Hajishengallis of the University of Pennsylvania. "You also have to return things to the way they were before the inflammatory destruction."

A new study led by Hajishengallis, the Thomas W. Evans Centennial Professor in Penn's School of Dental Medicine, and Triantafyllos Chavakis of the Technical University of Dresden has illuminated a key player in this resolution process, the protein Del-1, which the pair has studied extensively before. While prior research had underscored Del-1's role in curbing the initiation of inflammation, the new work finds that it can serve a very different function, actively working to clear inflammation. Which function the protein performs depends on the cell type that expresses it, the team found.

"Our findings prompted us to propose the 'location principle' in the spatial regulation of the immune response," says Chavakis. "In other words, homeostatic molecules—those responsible for maintaining equilibrium in the body—may perform different regulatory functions depending on their location."

The work appears in the journal Nature Immunology.

Hajishengallis, Chavakis, and their labs and collaborators have been interested in the protein Del-1 for many years. Through a series of experiments and publications, they've established its importance in the initiation of inflammation. Focusing on periodontitis, severe gum disease, as a model system, they've found Del-1 restrains the activity of neutrophils, preventing damaging inflammation and bone loss in the gums.

In the new work, they wanted to see whether Del-1 could also act not just to hold back inflammation from occurring in the first place but also to actively resolve it once it occurred.

In collaboration with co-author Jonathan M. Korostoff, professor of periodontics at Penn Dental Medicine, they found that, in humans with periodontitis, Del-1 levels rose upon treating the disease. To follow up on the finding and get at a mechanism, they turned to a mouse model of gum disease, observing that Del-1 expression levels rose when the animals' disease began to resolve, a mirror to the human data.

"Just because Del-1 goes up doesn't necessarily mean anything," says Hajishengallis, "but, when we did the same experiment with that lack Del-1, the resolution of inflammation failed."

That suggested to the scientists that Del-1 was a necessary component of the resolution process. To further explore this possibility, they turned to another disease, peritonitis, which involves inflammation of the abdominal lining.

Here they saw the same effect and were further able to show a course of action: Del-1 was able to act as a molecular bridge to expedite the clearance of dying neutrophils by connecting them to macrophages, a distinct type of immune cells that engulf and "eat" cellular debris, and thus maintaining a healthier environment. This process of clearing dying neutrophils is called efferocytosis.

Importantly, Del-1 appeared to reprogram the efferocytic macrophages toward a type that contributes to resolution and tissue repair. Mice lacking a domain of Del-1 that interacts with macrophages were not able to promote efferocytosis.

In addition to promoting this clearance of neutrophils, the researchers discovered that Del-1 also induced a group of molecular mediators called resolvins, which promote inflammation resolution. The researchers hypothesize that Del-1 may regulate a positive feedback loop, in which it triggers resolvins and then acts downstream of them to get things back in order after inflammation clears.

Perhaps the most novel finding of the paper, was what the researchers have termed the "location principle." In their earlier studies, they had found Del-1 secreted from endothelial cells that line tissues was responsible for regulating initiation of inflammation by inhibiting the traffic of neutrophils. But other work has shown that macrophages, too, could secrete Del-1. Using mice that overexpressed either the endothelial-derived Del-1 or the macrophage-derived Del-1, they found that the cell type mattered when it came to the protein's activity. Overexpressing Del-1 only in , for example, made no difference in the animals' ability to clear dying neutrophils in a model of peritonitis. Conversely, mice overexpressing Del-1 in their macrophages had no advantage in harnessing neutrophil recruitment but were better able to clear the neutrophils from the site of inflammation.

"This 'location principle' is novel," says Hajishengallis. "Tissues are not a sack of molecules; the geography is very important.

"As a pro-resolution protein, Del-1 is probably acting downstream of therapeutics that promote periodontal health," he adds. "For instance, the complement inhibitor AMY-101, which can cause a rise in Del-1 levels, may depend on Del-1 to accelerate the resolution of inflammation."

"This fundamental mechanism of clearance by Del-1," says Chavakis, "may also be involved in multiple inflammatory pathologies, including metabolic-inflammatory or malignant disease."

Explore further: Study blocks inflammatory bone loss in gum disease

More information: Ioannis Kourtzelis et al, DEL-1 promotes macrophage efferocytosis and clearance of inflammation, Nature Immunology (2018). DOI: 10.1038/s41590-018-0249-1

Related Stories

Study blocks inflammatory bone loss in gum disease

September 30, 2015
Periodontitis, a severe form of gum disease, doesn't just cause soft-tissue inflammation and bleeding. It also destroys the bone that supports the teeth. If it progresses unchecked, it can lead to tooth loss and is even associated ...

In cardiac injury, the NSAID carprofen causes dysfunction of the immune system

September 20, 2018
Non-steroidal anti-inflammatory drugs, or NSAIDs, are commonly used as inflammation blockers worldwide. However, recent clinical data show these painkillers can have serious side effects that create some risk of heart attacks, ...

Macrophages chase neutrophils away from wounds to resolve inflammation

December 8, 2014
Macrophages are best known for their Pac Man-like ability to gobble up cellular debris and pathogens in order to thwart infection. A new study in The Journal of Cell Biology describes how these immune cells also help resolve ...

Study blocks multiple sclerosis relapses in mice

November 11, 2014
In multiple sclerosis, the immune system goes rogue, improperly attacking the body's own central nervous system. Mobility problems and cognitive impairments may arise as the nerve cells become damaged.

A new mechanism in the control of inflammation

October 18, 2018
After infection or tissue injury, the inflammatory immune response attacks the infection and repairs the damaged tissue. However, sometimes excess inflammation can have the opposite effect, increasing injury in a process ...

Researchers reverse bone loss in immune disorder

March 26, 2014
Patients with leukocyte adhesion deficiency, or LAD, suffer from frequent bacterial infections, including the severe gum disease known as periodontitis. These patients often lose their teeth early in life.

Recommended for you

HIV vaccine protects non-human primates from infection

December 14, 2018
For more than 20 years, scientists at Scripps Research have chipped away at the challenges of designing an HIV vaccine. Now new research, published in Immunity, shows that their experimental vaccine strategy works in non-human ...

RNA processing and antiviral immunity

December 14, 2018
The RIG-I like receptors (RLRs) are intracellular enzyme sentries that detect viral infection and initiate a first line of antiviral defense. The cellular molecules that activate RLRs in vivo are not clear.

The 'greying' of T cells: Scientists pinpoint metabolic pathway behind age-related immunity loss

December 13, 2018
The elderly suffer more serious complications from infections and benefit less from vaccination than the general population. Scientists have long known that a weakened immune system is to blame but the exact mechanisms behind ...

Scientists create most accurate tool yet developed to predict asthma in young children

December 13, 2018
Scientists at Cincinnati Children's Hospital Medical Center have created and tested a decision tool that appears to be the most accurate, non-invasive method yet developed to predict asthma in young children.

New genetic study could lead to better treatment of severe asthma

December 12, 2018
The largest-ever genetic study of people with moderate-to-severe asthma has revealed new insights into the underlying causes of the disease which could help improve its diagnosis and treatment.

Researchers discover unique immune cell likely drives chronic inflammation

December 11, 2018
For the first time, researchers have identified that an immune cell subset called gamma delta T cells that may be causing and/or perpetuating the systemic inflammation found in normal aging in the general geriatric population ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.