"Unexpected finding" aids understanding of inflammation

Scientists at Trinity College Dublin (TCD) have made an important breakthrough in understanding how inflammation is regulated, which could impact our response to autoimmune disorders.

Our immune system works to protect us from infection and injury, however, when immune responses become too aggressive this can lead to damaging inflammation. This occurs in conditions such as rheumatoid arthritis and psoriasis.

Inflammation is triggered when our bodies produce “alarm proteins” (interleukins), which ramp up our defenses against infection and injury by switching on different components of our immune system. 

Understanding how and when such alarm proteins are produced and how they activate our immune system has led to major breakthroughs in the treatment of many immune conditions.

Scientists at TCD have just discovered that a key immune alarm protein previously believed to calm down the immune response actually does the opposite.

The team from the Smurfit Institute of Genetics at TCD, led by Prof Seamus Martin, found that Interleukin-37 has an unexpected function as an immune-activating molecule. Previous studies suggested that this interleukin instead served as an “off switch” for the immune system.

“Interleukins play key roles in regulating our immune systems in response to bacterial and fungal infections. However, Interleukin-37 has long remained an enigma, as it isn’t found in mammals such as mice. This has presented a major obstacle to figuring out what it does as much of what we know about the human immune system has first been discovered in model organisms whose biological make-ups are similar to ours,” Prof Martin explained.

Prior to this new study, Interleukin-37 was thought to have immune-suppressive functions, but how exactly it switched off inflammation was hotly debated. However, the TCD team found that when activated in the correct way, Interleukin-37 displays potent pro-inflammatory activity.

Prof Martin said that this pro-inflammatory activity was “highly unexpected”.

“Our work shows that the protein binds to an interleukin receptor in the skin that is known to play a key role in driving psoriasis. And, to add further intrigue to the story, this brings the total number of immune alarm molecules that signal via this particular interleukin receptor to four.

“Why there are so many interleukins that bind to the same receptor is a mystery, but if we were to speculate it may be because this receptor serves a very important sentinel function in our skin, and that one alarm protein may simply not be enough to respond to the many different infectious agents that our skin encounters,” he explained.

He noted that skin is the “major barrier between our bodies and the outside world that microbes must breach if they are to gain entry to our bodies”. As a result, it can be considered the first line of defense in our immune system.

The scientists suggested that Interleukin-37 and other immune alarm proteins may have evolved to become distinct variations on the same theme that enable our bodies to detect different types of infection by becoming activated by enzymes that are distinct to each infectious agent. 

The research involved a collaboration between several TCD research groups led by Prof Martin's team, which included post-doctoral scientists Dr Graeme Sullivan and Dr Pavel Davidovich, along with research groups led by Prof Ed Lavelle (School of Biochemistry and Immunology) and Prof Pat Walsh (School of Clinical Medicine).

The findings have been published in the journal, Science Immunology.