Unearthing a new form of toxic inflammation

Hudson Institute scientists have discovered how a molecule is transferred between damaged cells and healthy immune cells, which might cause toxic inflammation in a host of diseases.

This toxic inflammation is at the root of several inflammatory diseases and autoimmune conditions—yet the process by which the small inflammatory molecule, cGAMP, is transferred from a damaged cell to a healthy cell is not well known.

Systemic lupus erythematosus (SLE)—more commonly known as lupus—is one such disease, which results from a malfunctioning immune system (an autoimmune disease). It causes inflammation, swelling, and damage to the joints, skin, kidneys, heart and lungs—and affects over 20,000 people in Australia and New Zealand.

SLE is a progressive disease with episodic flares, which are associated with accrual of irreversible organ damage. Regrettably, the cause of flares (when symptoms worsen) in SLE is unknown, but it is clear that sunlight exposure is important in systemic as well as skin disease exacerbation.

Dr Michael Gantier, Research Group Head of the Nucleic Acids and Innate Immunity group.

What did the researchers discover?

Hudson Institute’s Dr Michael Gantier, Research Group Head of the Nucleic Acids and Innate Immunity group, led a study published in mBio which demonstrated the first direct evidence that cGAMP can be transferred from a damaged cell to a healthy immune cell through proteins called connexins.

Connexins are proteins that form channels to link adjacent cells together. Existing drugs are known to selectively inhibit these channels, and are currently being used to treat other conditions—for instance Meclofenamate combats menstrual period pain.

Dr Gantier and his team believe that repurposing these approved drugs would mean that the process by which toxic inflammation is amplified in autoimmune conditions such as lupus can be targeted.

“A major problem of anti-inflammatory drugs is their lack of selectivity—the sledgehammer approach—which can lead to hypersensitivity against infections,” said Dr Gantier.

“By selectively targeting the process through which toxic inflammation is amplified, we do not compromise the rest of the immune response to infection, while preventing flare-ups—a crucial part of disease progression which can cause tissue damage.”

What does the future look like?

Dr Gantier says the next step is to test connexin-inhibitor drugs such as Meclofenamate in preclinical models, with the long-term goal of developing a treatment with even greater selectivity.

What happens during sunlight exposure?

For people with lupus, upon sun light exposure, their cells are put under stress, become damaged, and subsequently produce a small inflammatory molecule called cGAMP.

Once cGAMP is produced, scientists believe that it is transferred between the damaged cells and healthy immune cells, which amplifies inflammation.

Usually, this local inflammation is useful in helping the body fight off infection (signalling to the immune system that something is wrong), yet it can be toxic for people with autoimmune diseases such as lupus.

Collaborators

Monash Health, Monash University, Walter and Eliza Hall Institute of Medical Research (WEHI), CSIRO.

Funders

The Australian National Health and Medical Research Council (NHMRC), the Australian Research Council (ARC), the Québec Fonds de Recherche du Québec (FRQS)—Santé.

Research Group leading this work