Worms solve mystery of key inflammatory molecule implicated in asthma, eczema and more

Mouse
Mice lacking myeloid-derived IL-33 were able to quickly clear hookworm and roundworm infection, a finding that could improve efforts to target IL-33 in treating inflammatory diseases. (Pixabay)

IL-33 is a cytokine that’s known to have a dual role in the body: It can either dial up the immune response or turn it down. And it has been shown to be a key player in inflammatory diseases such as asthma and eczema as well as other conditions including obesity.

Now, scientists led by the University of Pennsylvania’s veterinary school have discovered that IL-33’s activity is governed by the type of cell that produces it. The finding—made with the help of parasitic worms—could aid efforts to develop IL-33-targeted therapies, they argued in the journal Science Immunology.

The team started by studying two groups of mice: one in which IL-33 was released only by immune cells known as myeloid cells and another in which it only came from epithelial cells, or cells that line mucosal surfaces like those in skin and organs. They infected both groups with hookworms.

Free Webinar

From Patient Adherence to Manufacturing Ease - Why Softgels Make Sense for Rx

Join Thermo Fisher Scientific’s upcoming webinar to learn why softgels offer numerous benefits for Rx drug development, including enhanced bioavailability, patient compliance and easy scale-up. Register Today.

They found that mice lacking myeloid-derived IL-33 cleared the hookworm infection quickly, but those without epithelial IL-33 did not. The same was true in animal models of roundworm infection.

The researchers drilled down further and discovered that a subset of myeloid cells, dendritic cells, produce IL-33. That IL-33 supported regulatory T cells (Tregs), "whose whole purpose is to suppress the immune response," said co-author De'Broski Herbert, Ph.D., associate professor of pathobiology at Penn, in a statement.

They went on to identify a specific protein, perforin-2, which promotes the release of IL-33 from dendritic cells. Eliminating the protein from the cells prevented the growth of Tregs, they reported.

RELATED: U.K. team sheds light on how AnaptysBio's anti-IL-33 eczema drug tamps down inflammation

The role of IL-33 in inflammatory diseases is well known, but efforts to target the cytokine have produced mixed results. Last year, Sanofi and Regeneron’s antibody targeting IL-33, REGN3500, met its primary endpoint in a phase 2 asthma trial, but it didn’t outperform Dupixent, the two companies’ blockbuster drug that targets IL-4 and IL-13.

AnaptysBio raised $80 million in an initial public offering in 2017 to bring its IL-33 antibody into late-stage testing in eczema. It failed in midphase testing in that disease, but the company is continuing to study it in patients who have chronic rhinosinusitis with nasal polyps.

The Penn team did find a link between perforin-2 and rhinosinusitis. In samples of polyps from patients, they discovered the protein in cell membranes.

The study, Herbert concluded, “opens up a whole new direction for understanding how [IL-33] could be involved” in a range of inflammatory diseases.

Suggested Articles

GE Healthcare has launched a new algorithm that can read X-rays and help assess the correct placement of ventilator tubes in critical patients.

Months after approving a COVID-19 shot based on early data, Russia is reporting data from nearly 19,000 people showing it is more than 90% effective.

Early-stage biotech Elevian has raised $15 million as it looks to target multiple age-related diseases.