The immune system's raison d'être is to protect us from invading microbes. But in the intestines, at least, its chances of encountering bad bugs, which necessitate a vigorous response, are, if not exactly as rare as a lightning strike, then nevertheless the exception rather than the rule.

Instead, the typical bug that the immune system encounters in the gut is a harmless or even beneficial commensal – which leads rather naturally to the question of how, exactly, immune system cells can tell the difference.

Researchers have found part of the answer to this mystery. Intestinal macrophages do not respond to signals that stimulate Toll-like receptors, which makes them more or less blind to commensals. But they can sense pathogens through the NRLC4 inflammasome, a complex of proteins that sets off an inflammatory response when it is activated. Several different types of inflammasome exist, and the NRLC4 version does not need Toll-like receptors for its activation.

The findings, Gabriel Nùñez told BioWorld Today, are "the first clear-cut example of how the immune system delineates between a pathogen and a commensal." Nùñez is a professor of pathology at the University of Michigan, and the senior author of the paper describing the studies, which is slated for publication in the May 2012 issue of Nature Immunology after advance online publication.

One way the innate immune system identifies invaders is by sensing so-called "pathogen-associated" molecular patterns (PAMPs) that activate Toll-like receptors. PAMPs are indeed expressed by pathogens. But not exclusively so. Commensal gut bacteria express them, too.

In their studies, Nùñez and his team first looked at the responses of intestinal macrophages to such PAMPs. They found that such PAMPs generally left that type of macrophage cold, which meant, he elaborated, that "typically, they cannot sense the commensals." Instead, intestinal macrophages "are mostly involved in keeping everything quiet" under normal circumstances.

When Nùñez and his team infected the mice with Salmonella bacteria, however, it was a different story. The macrophages sprang into action, producing the proinflammatory cytokine interleukin-1beta after their NRLC4 inflammasome was activated by the Salmonella's secretion system.

Once macrophages produced the interleukin, it bound to endothelial cells that line the small blood vessels in the gut. There, it attracted neutrophils, which crossed into the gut and made short work of the Salmonella. Mice lacking either inflammasome proteins or the ability to produce IL-1beta had a higher death rate when they were infected with Salmonella, although the details depended on the mouse strain.

For now, Nùñez and his team are more concerned with understanding the basic mechanisms of how the immune system tells friend from foe than with drug discovery efforts based on the findings. Nùñez noted that "there must be similar mechanisms for other pathogens," which his team hopes to discover.

But when asked about the practical implications of his team's work, he did point out that the work suggested that patients being treated with IL-1beta blockers need to be monitored carefully for infection.

In addition to general IL-1 inhibitors, IL-1beta-specific inhibitors in development include XOMA Ltd.'s gevokizumab (formerly XOMA 052), Eli Lilly and Co.'s LY2189102 and Amgen Inc.'s AMG 108, which are being developed for multiple indications including diabetes. Some analysts believe that IL-1 targeting is a space that could support multiple blockbusters. (See BioWorld Today, Jan. 10, 2011.)

Ilaris (canakinumab, Novartis AG), which is approved for the treatment of anti-inflammatory syndromes that collectively go by the name cryopyrin-associated periodic syndrome, does include a warning about an increased risk of serious infections on its label. And that risk was part of what prevented the FDA from approving it for gouty arthritis, though additional trials are ongoing. (See BioWorld Today, June 22, 2011.)

The data now published in Nature Immunology showed one reason for that risk, and, Nùñez said, illustrated a more general principle about proinflammatory signals.

"These molecules were not made to give us disease. They were made to protect us," he said. If a patient gets a Salmonella infection while being treated with IL-1beta blockers, "they will be in real trouble."