RARE Daily

Researchers Find Genetic Switch Underlying Rare Inflammatory Diseases

March 25, 2024

Rare Daily Staff

Researchers have discovered how the body’s inflammation machinery can get stuck and cause rare genetic inflammatory diseases.

Kate Schroder and her team at the University of Queensland’s Institute for Molecular Bioscience have been studying the NLRP3 inflammasome, a protein complex that drives inflammation.

Autoinflammatory diseases occur when the body creates an immune response without a cue, ranging from very mild inflammation such as a rash, to life-threatening inflammatory responses leading to fever, blindness, deafness, and cognitive decline.

“The inflammasome protects us during infection by triggering an immune response, but it can also go wrong and cause uncontrolled inflammation and disease,” said Schroder. “In those patients, there are mutations that stick the inflammasome on/off switch in the ‘on’ position, so it is always firing, causing inflammation driven by a mutation instead of an infection or wound. The inflammation also can’t be turned off without drug intervention.”

The body’s NLRP3 inflammasome is involved in neurogenerative diseases including Alzheimer’s, inflammatory diseases such as arthritis, and cancer and gout.

Schroder’s team found NLPR3 can be switched on permanently by a mutation in the protein NLRP12, with further tests revealing that NLRP12 also acts as a natural inhibitor to control NLRP3. They published their findings in the journal Science Signaling.

“The two proteins are very closely related within the same family and like many siblings, one tries to control the other and stop it from doing what it wants to do,” said Schroder

Because NLRP12 exists naturally in our cells, NLRP12 modulators may provide an effective treatment for people with autoinflammatory disease associated with overactive inflammasome NLRP3 signaling.

There are multiple NLRP3 inhibitors that are currently being tested in clinical trials including one developed by Schroder’s team. She said with the discovery that NLRP12 turns off NLRP3, the team seeks to make further inroads to understand these diseases.”

Photo: Kate Schroder, professor at the University of Queensland


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