Summary: SARM, an ancient immune protein previously implicated in apoptosis, is a key immune regulator in peripheral immune cells. The finding could help in the development of treatments for a range of diseases, including Alzheimer’s, cancer and diabetes.
Source: Trinity College Dublin
Scientists from Trinity College Dublin have discovered a potential new target for regulating inflammation, which drives a range of diseases including diabetes, cancer and Alzheimer’s. The potential target is an ancient immune protein – SARM – that has been conserved throughout evolution and thus is very similar in humans, other mammals, flies and worms.
The scientists, from Trinity’s School of Biochemistry and Immunology based at the Trinity Biomedical Sciences Institute (TBSI), discovered a previously unknown but important role that SARM plays in the immune response. Their work has been published today in the prestigious journal Immunity.
The innate immune system and SARM
The innate 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. This innate immune activation leads to inflammation. However, excessive and/or inappropriate inflammation is implicated in a range of debilitating diseases and so controlling inflammation presents a major problem that scientists are trying to solve.
Specifically, it is inflammasomes – tiny molecular machines – that assemble inside immune cells after sensing infection or injury and initiate the inflammatory response. When assembled, inflammasomes trigger 1) the release of an inflammatory mediator (interleukin-1, or IL-1) and 2) instigate an inflammatory form of cell death (pyroptosis).
Both of these actions can drive inflammation, but what controls the amount of IL-1 produced and the extent of pyroptosis that occurs during inflammation was previously unknown. It turns out that SARM is a key inflammasome regulator.
In their study, the scientists showed that 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.
The work, which was funded by Science Foundation Ireland, was conducted by scientists in Professor Andrew Bowie’s research group, in particular, co-first authors Dr Michael Carty and Dr Jay Kearney. Other TBSI scientists involved include Professors Ed Lavelle and Padraic Fallon.
Dr Michael Carty, the lead author of the study, said: ”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.”
Professor of Innate Immunology at Trinity, Andrew Bowie, added: “Scientists already knew that SARM drives cell death in the brain, and as a result, it is being investigated as a therapeutic target for neurodegeneration and related diseases, 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.”
Cell Survival and Cytokine Release after Inflammasome Activation Is Regulated by the Toll-IL-1R Protein SARM
Highlights • NLRP3 inflammasomes stimulate IL-1β release either with or without cell death • The TIR protein SARM negatively regulates NLRP3 to reduce IL-1β release • SARM-mediated mitochondrial depolarization (MDP) is required for optimal pyroptosis • NLRP3 activators that don’t kill cells fail to cause SARM-dependent MDP
Summary Assembly of inflammasomes after infection or injury leads to the release of interleukin-1β (IL-1β) and to pyroptosis. After inflammasome activation, cells either pyroptose or enter a hyperactivated state defined by IL-1β secretion without cell death, but what controls these different outcomes is unknown. Here, we show that removal of the Toll-IL-1R protein SARM from macrophages uncouples inflammasome-dependent cytokine release and pyroptosis, whereby cells displayed increased IL-1β production but reduced pyroptosis. Correspondingly, increasing SARM in cells caused less IL-1β release and more pyroptosis. SARM suppressed IL-1β by directly restraining the NLRP3 inflammasome and, hence, caspase-1 activation. Consistent with a role for SARM in pyroptosis, Sarm1 −/− mice were protected from lipopolysaccharide (LPS)-stimulated sepsis. Pyroptosis-inducing, but not hyperactivating, NLRP3 stimulants caused SARM-dependent mitochondrial depolarization. Thus, SARM-dependent mitochondrial depolarization distinguishes NLRP3 activators that cause pyroptosis from those that do not, and SARM modulation represents a cell-intrinsic mechanism to regulate cell fate after inflammasome activation.