BioWorld International Correspondent

LONDON - A molecule that acts as a natural brake on an important immune response could hold clues to new ways of treating sepsis - the potentially fatal overactivation of the immune system that can follow some infections.

The discovery of the molecule's role also will have implications for those studying ways of treating autoimmune diseases such as rheumatoid arthritis, as these also are due to an excessive immune reaction against the body's own tissues.

Andrew Bowie, senior lecturer in the School of Biochemistry and Immunology at Trinity College in Dublin, Ireland, told BioWorld International: "We have identified a new and important way in which the body can control the immune response. It is important to understand how the body itself turns off these pathways, since we can then try to use that knowledge to try therapeutically to turn them off in appropriate contexts."

The work is reported in Nature Immunology (published online Sept. 10), in a paper titled "The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling."

Bowie and his colleagues have been studying a core feature of the innate immune system - the Toll-like receptors (TLRs) that detect the presence of bacteria and viruses. TLRs are pattern-recognition molecules on cells such as macrophages and dendritic cells, which bind microbial products.

When those receptors become activated, a signaling cascade is turned on, resulting in production of many types of molecules including interferons and cytokines, such as tumor necrosis factor alpha. It is that response that can lead to sepsis.

Recent research has shown that, inside the cell, the first stage in the signaling process is for molecules called TIR adaptor proteins to bind to the TLR.

Out of the five TIR adaptor proteins so far identified, the first four have all been shown to play roles in transmitting the signal to activate the immune response into the cell. Little was known about the fifth, which is called SARM.

The paper by Bowie and his colleagues showed that SARM is a negative regulator of Toll-like receptor signaling. Bowie said: "This finding is important because the first four of this family of signalling molecules were all involved in turning on the immune response, so we were surprised to find that the fifth was involved in suppressing the pathway. Clearly, SARM represents an important brake on the immune response."

Experiments carried out by the team showed that SARM targets only two of the known Toll-like receptors. One of these is TLR4, the receptor that triggers the response to lipopolysaccharide (a component of bacterial cell walls), which can develop into septic shock. The other is a receptor that is involved in detecting the presence of viruses.

Adding lipopolysaccharide to human blood cells causes activation of TLR4. When Bowie and his colleagues did this, they also found that levels of SARM rose. "This suggests that the body does indeed use SARM as a way of putting a brake on this response," Bowie said.

The researchers also knocked down expression of SARM in human blood cells using small interfering RNA. "We found that when we did this, we got a much larger increase in production of tumor necrosis factor alpha from lipopolysaccharide-treated cells than when SARM was available at normal levels. This provides a clear link to the body's response to sepsis, which involves heightened levels of tumor necrosis factor alpha," Bowie added.

Bowie suggested that it might be possible to find a way to mimic what SARM does, or enhance the function of SARM. Such therapeutics could possibly suppress activation of the immune system in a similar way to SARM.

Next, the group wants to investigate further how SARM binds to a protein called TRIF, which is one of the other four adaptor proteins. Bowie said: "We are starting to use different techniques to screen for other proteins that might be interacting with SARM. We have identified some proteins already that might explain how SARM inhibits these pathways."

SARM also is highly expressed in mouse brain, so the team plans to investigate how it might be involved in the immune response in the brain.