Immune surprise: newly evolved alarm molecule

Inflammatory cytokines

image: Human cells expressing inflammatory cytokines (stained green).
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Credit: Professor Martin Laboratory; Trinity College Dublin

Scientists at Trinity College Dublin have made a breakthrough in understanding how inflammation is regulated. They have just discovered that a key immune alarm protein previously thought to calm the immune response actually does the opposite.

Their work has numerous potential impacts, especially in the context of understanding and responding to autoimmune disorders and inflammation.

While our immune system plays a very important role in protecting us from infection and injury, when immune responses become too aggressive this can lead to harmful inflammation, which occurs in conditions like rheumatoid arthritis and psoriasis. Inflammation is triggered when our bodies produce “alarm proteins” (interleukins), which increase our defenses against infection and injury by activating different components of our immune system.

Understanding how and when these alarm proteins are produced and how they activate our immune system has led to great advances in the treatment of many immune diseases.

Now, scientists at Trinity College Dublin’s Smurfit Institute of Genetics, led by Seamus Martin, Smurfit Professor of Genetics, have discovered that interleukin-37 has an unexpected role as an immune system activating molecule, as previous studies suggested that it this interleukin served as an “off switch” for the immune system.

Professor Martin said:

“Interleukins play a key role in regulating our immune system in response to bacterial and fungal infections. However, interleukin-37 has long been an enigma, as it is not found in mammals such as mice. This has presented a major obstacle to finding out what it does, as much of what we know about the human immune system was first discovered in model organisms whose biological makeup is similar to ours.”

Before the new study, interleukin-37 was thought to have immunosuppressive functions, but exactly how it stopped inflammation was hotly debated. However, Trinity scientists now report that, when activated in the correct way, interleukin-37 displays potent pro-inflammatory activity.

Professor Martin additional:

“This pro-inflammatory impact was very unexpected. Our work shows that the protein binds to an interleukin receptor in the skin that is known to play a key role in the development of psoriasis. And, to add more intrigue to the story, this brings to four the total number of immune alarm molecules that signal via this particular interleukin receptor.

“Why there are so many interleukins that bind to the same receptor is a mystery, but if we were to speculate, it could be because this receptor serves a very important sentinel function in our skin, and that alarm protein may simply not be enough to respond. to the different infectious agents that our skin encounters. Our skin is the main barrier between our body and the outside world that microbes must cross to gain entry into our bodies, and in many ways it represents our immune system’s first line of defense.”

As such, interleukin-37 and other immune alarm proteins may have evolved to be different variations on the same theme that allow our bodies to detect different types of infection when activated by enzymes that are different for each infectious agent.

The research has just been published in the internationally renowned journal, immunology Science, and was a collaboration between several Trinity research groups led by Professor Martin’s team, which included postdoctoral scientists Dr Graeme Sullivan and Dr Pavel Davidovich, together with research groups led by Professor Ed Lavelle (School of Biochemistry and Immunology) and Professor Pat Walsh (School of Clinical Medicine).

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