Irish scientists pinpoint potential new way to tackle inflammation

A potential new way to control inflammation, which drives a range of diseases including diabetes, cancer and Alzheimer’s, has been identified by Irish scientists.

The target is “an ancient immune protein” – known as SARM – that has been conserved throughout evolution, and as a consequence is similar in humans, other mammals, flies and worms, according to a research team at TCD.

The researchers at the Trinity Biomedical Sciences Institute (TBSI) have discovered a previously unknown but important role SARM plays in immune responses.

The immune system is activated as a protective mechanism in response to cells “sensing the presence of strangers such as bacteria and viruses, or of dangers such as tissue injury”. When activated, it leads to inflammation.

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However, excessive and/or inappropriate inflammation is implicated in a range of debilitating diseases, so controlling it presents a major medical problem scientists are trying to solve.

Specifically, tiny molecular machines known as inflammasomes assemble inside immune cells after sensing infection or injury, and initiate the inflammatory response. When assembled, they trigger the release of an inflammatory mediator (IL-1) and instigate an inflammatory form of cell death (pyroptosis).

Both of these actions can drive inflammation, but what controls the amount of the inflammatory mediator IL-1 produced and the extent of pyroptosis that occurs during inflammation was previously unknown. It turns out that the immune protein SARM is "a key inflammasome regulator", explained Prof Andrew Bowie of TBSI.

The more SARM that cells contain, the less IL-1 they produce, because SARM interferes with inflammasome assembly. “Conversely, more SARM leads to more cell death since SARM causes significant damage to mitochondria; the energy producers of the cell,” he added, “So if you block SARM, you block other types of cell death.”

The TCD researchers have shown inflammation due to sepsis is caused by cell death, so reducing SARM can suppress the condition.

"We've been working to try to unlock the secrets of what this ancient protein does for some time, and it was a surprise to find that it could be a key regulator of the inflammasome, which may implicate SARM in inflammatory diseases." said lead author Dr Michael Carty.

Scientists already knew that SARM drives cell death in the brain, and as a result it is being investigated as a therapeutic target for treatment of neurodegeneration and related diseases, Prof Bowie added.

“But here we found that it is also a key immune regulator in peripheral immune cells. This discovery gives us hope that if we can successfully target SARM we may be able to regulate inflammation, which would provide a new option for treating a plethora of diseases.”

Their research, published on Tuesday in the journal Immunity, is funded by is Science Foundation Ireland. Dr Jay Kearney and Profs Ed Lavelle and Padraic Fallon who are also based at TBSI contributed to the study.