How do cells release IL-1? After three decades, now we know

November 28, 2017, Children's Hospital Boston
In hyperactivated macrophages, gasdermin D forms a limited number of pores -- enough to release IL-1 but not enough to kill the cell through pyroptosis. The macrophages stay alive and retain their phagocytic capacity, continuing to ingest microbes while stimulating memory T-cell formation via IL-1. Other proteins, like the cytokine TNF-alpha, are released through the classic secretion-signal pathway. Credit: Charles Evavold, Boston Children's Hospital

Researchers at Boston Children's Hospital have identified, for the first time, the molecule that enables immune cells to release interleukin-1 (IL-1), a key part of our innate immune response to infections. Findings were published online today by the journal Immunity.

IL-1, first described in 1984, is the original, highly potent member of a large family of cellular signaling molecules called cytokines, which regulate immune responses and inflammation. Several widely used anti-inflammatory drugs, such as anakinra, block IL-1 to treat such conditions as rheumatoid arthritis, systemic inflammatory diseases, gout and atherosclerosis. IL-1 is also a target of interest in Alzheimer's disease.

Yet until now, no one knew how it gets released by our .

"Most proteins have a secretion signal that causes them to leave the cell," says Jonathan Kagan, PhD, an immunology researcher in Boston Children's Hospital's Division of Gastroenterology and senior author of the new study. "IL-1 doesn't have that signal. Many people have championed the idea that IL-1 is passively released from : you just die and dump everything outside."

Recent work elsewhere at Boston Children's, for example, demonstrated that a protein called gasdermin D punches holes in the membranes of by forming pores. This releases IL-1 and other cytokines—but it also kills the cell, through an inflammatory cell-death program called pyroptosis.

In the new study, Kagan and first author Charles Evavold showed that gasdermin D also enables the release of IL-1 from living immune cells.

Dead macrophages (stained blue) don't make good infection fighters, unlike their living kin (green). It turns out macrophages don't need to die in order to release IL-1. Credit: Charles Evavold, Boston Children's Hospital

Stayin' alive

The idea of all immune cells sacrificing themselves to deliver IL-1 never seemed right to Kagan. Immune cells need to stay alive to carry out their other jobs, like stimulating the formation of memory T cells that provide long-lasting protective immunity.

Last year, Kagan, Ivan Zanoni, PhD, and colleagues reported in Science that IL-1 can be released from living dendritic cells, immune cells that present antigens to T cells. They showed that dendritic cells can enter a hyperactivated state in which they secrete IL-1, boosting their ability to rally memory T cells. But the question of how IL-1 gets released remained unanswered.

The new study involved hyperactivated macrophages, immune cells that engulf and ingest pathogens. "We found, in hyperactivated cells, that gasdermin forms enough pores to let IL-1 pass through, but not enough to kill the cell," says Kagan.

These living macrophages release IL-1, ingesting fungi (stained red) all the while. The bright green spots are inflammasomes, large protein complexes that detect danger signals and stimulate gasdermin D to form pores allowing IL-1 to pass through. Credit: Charles Evavold, Boston Children's Hospital

A path to better vaccine adjuvants?

The immune response is like a yin-yang: If it's too weak, you're susceptible to infections; if it's too strong, the system can tip toward autoimmune disease and, in the face of a serious infection, sepsis.

Gasdermin D inhibition is under study as a way of curbing inflammation-related diseases and sepsis. But Kagan's team is looking at the flip side, exploring gasdermin D as a target for stimulating IL-1 release from living, working cells to make vaccines more potent and long-lasting.

"For strong vaccination, you need to activate memory T cells, so you need a way to release IL-1 from living cells," says Kagan.

Interestingly, recent work shows that alum, the primary vaccine adjuvant in use today, works by activating inflammasomes. Inflammasomes are large protein complexes in that detect danger signals—and they're known to activate gasdermin D and pyroptosis.

Could gasdermin D be stimulated directly, in a way that does not kill the cell, to allow IL-1 out and dial up the to vaccines? That's the idea Kagan's lab is exploring now. The lab is also exploring how a lipid called oxPAPC, which hyperactivates , supercharges memory T-cell activation by promoting IL-1 release through gasdermin D pores.

Explore further: Can we hypercharge vaccines? Tapping a chemical we already make could enhance T-cell production

Related Stories

Can we hypercharge vaccines? Tapping a chemical we already make could enhance T-cell production

April 21, 2016
Researchers at Boston Children's Hospital report that a fatty chemical naturally found in damaged tissues can induce an unexpected kind of immune response, causing immune cells to go into a "hyperactive" state that is highly ...

A new angle for countering severe bacterial infections and sepsis

July 6, 2016
Bacterial infections that don't respond to antibiotics are of rising concern, as is sepsis—the immune system's last-ditch, failed attack on infection that ends up being lethal itself. Reporting online in Nature on July ...

Savior of T-cells may be enemy of liver immune cells

April 24, 2017
Researchers at Houston Methodist demonstrated that a surface protein called OX40, responsible for keeping one type of immune system cell alive, can trigger the death of liver immune cells, in turn starting a chain reaction ...

Researchers makes 'natural born killer' cell discovery

August 31, 2017
An unexpected role for a white blood cell called the Natural Killer (NK) cell - a critical cell for ridding the body of infection and cancer, has been discovered by researchers at New Zealand's University of Otago.

Cells that die with a bang contribute to high death rate in bloodstream infections

October 10, 2017
Cells lining blood vessels in the lungs that are exposed to bacterial toxins don't die easy, according to a new study led by researchers at the University of Illinois at Chicago College of Medicine.

Recommended for you

Immune signature predicts asthma susceptibility

February 16, 2018
Asthma is a chronic inflammatory disease driven by the interplay of genetics, environmental factors and a diverse cast of immune cells. In their latest study, researchers at La Jolla Institute for Allergy and Immunology (LJI) ...

Scientists identify immune cascade that fuels complications, tissue damage in chlamydia infections

February 13, 2018
Closing a critical gap in knowledge, Harvard Medical School scientists have unraveled the immune cascade that fuels tissue damage and disease development in chlamydia infection—the most common sexually transmitted disease ...

Mouse study adds to evidence linking gut bacteria and obesity

February 12, 2018
A new Johns Hopkins study of mice with the rodent equivalent of metabolic syndrome has added to evidence that the intestinal microbiome—a "garden" of bacterial, viral and fungal genes—plays a substantial role in the development ...

Cancer killing clue could lead to safer and more powerful immunotherapies

February 12, 2018
New research could help to safely adapt a new immunotherapy—currently only effective in blood cancers—for the treatment of solid cancers, such as notoriously hard-to-treat brain tumours.

Mechanism behind autoimmune disorder revealed

February 7, 2018
Northwestern Medicine scientists discovered a previously-unknown mechanism of disease behind a specific autoimmune disorder, findings published in the Proceedings of the National Academy of Sciences.

Study shows how body prevents potentially useful bacteria from causing disease

February 7, 2018
A new study reveals a mechanism by which the immune system may decide whether a bacterial species is a partner in bodily processes or an invader worthy of attack.

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.