A New Inflammatory "Danger" Signal Spotted and Stopped

When you drive a car, sometimes it's fine to just chug along. But if there's a threat you might suddenly have to take action to get out of trouble. Could it be similar for front-line immune cells called macrophages when an infection tries to take hold?

A new study suggests that unthreatened macrophages tick over on one form of core metabolism, oxidative phosphorylation. But throw a bacterial threat into the mix and that metabolism switches over to a form called aerobic glycolysis, and you see an inflammatory response.

Prof Luke O'Neill from Trinity College Dublin likens the switch to what happens in a hybrid car when it changes from using electricity as a source of energy to burning petrol instead. And he and colleagues have just mapped out how a bacterial signal can flip the macrophage 'engine' from oxidative phosphorylation to glycolysis.

You could extend that hybrid-car analogy even further. Macrophages in the blood have the job of 'sensing' potential threats such as bacteria and then engulfing them. So perhaps they are like hybrid police cars, keeping watch and responding when there's a threat.

The study found that if you expose macrophages to lipopolysaccharide - a signal of bacterial threat - the LPS binds to a toll-like receptor on the surface of the macrophage. This is an early signal of trouble, much like the message coming in over the police radio.

Then the core metabolism in the macrophage changes from oxidative phosphorylation to glycolysis, the equivalent of putting the boot down and switching the energy source in the hybrid engine.

"If there's a bacterial invader threatening an infection, then you want the macrophages to become active, this is a good thing," says O'Neill, who is Director of the Trinity Biomedical Sciences Institute.

As well as the switch to glycolysis, you also see an inflammatory response, and O'Neill believes they have found an important cog in the mechanism: succinate.

"When macrophages make that switch there is also a rise in the metabolite succinate, and this acts as a danger signal that turns on the pro-inflammatory cytokine interleukin-1ss," he explains.

Succinate also appears to alter the shapes of several proteins in the macrophages, though it's not known exactly what effect this has - there is plenty yet to discover. "I would anticipate that these proteins are activated through this succinylation process, but that is something we are going to look at now," says O'Neill.

In other words, succinate seems to act as the police car's siren, spreading the news that a response is needed and triggering it in the form of inflammation.

Of course this activation and inflammation can be helpful when there's a threat to fight off. But too much of an inflammatory response is not such good news: if it runs on for too long you can get chronic inflammation, or if the response is overzealous, it can result in potentially life-threatening sepsis.

So the researchers also looked at ways to reduce the inflammation, and found that they were able to inhibit interleukin-1ss expression in the model by interfering with the switch to glycolysis.

They were also able to tone down the inflammatory response with an anti-epilepsy medication called vigabatrin. "We tried that because the drug interferes with a pathway by which the macrophages are making succinate," explains O'Neill. "And we saw that the drug protected mice from a serious immune reaction called sepsis."

Dampening down the macrophage's ability to respond might not be such a great idea for people in good health, but being able to cut the inflammatory ramp-up could point to new treatments for acute and chronic inflammatory conditions, according to O'Neill. "It's very exciting because we now have a new way to interfere with the production of interleukin-1, which is implicated in several conditions, including diabetes," he says.

The findings could also offer insight on the relationship between inflammation and cancer, he adds, because glycolytic metabolism is also seen in tumor cells - the Warburg effect - and cancer and inflammation go hand in glove. "There is a parallel here, the same peculiar metabolism is kicking off in tumors as we see in macrophages," says O'Neill.

Co-author Prof Cormac Taylor, from University College Dublin, agrees that the study highlights the links between biochemical pathways that we typically associate with metabolism, immunity and disease. "What has become really important recently is the recognition of the key role of cross-talk between the pathways regulating metabolism, inflammation and tumor development," he says. "And this is one of the clearest examples where there is a direct interface between inflammation and the type of metabolism we see in cancer."

Reference: Tannahill et al., Succinate is an inflammatory signal that induces IL-1? through HIF-1?. Nature. 2013 Mar 24. doi: 10.1038/nature11986

Image: Denis Klein

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