When we think about the immune system, we usually associate it with fighting infections. However, a study published inย Scienceย by the Champalimaud Foundation reveals a surprising new role. During periods of low energyโsuch as intermittent fasting or exerciseโimmune cells step in to regulate blood sugar levels, acting as the โpostmanโ in a previously unknown three-way conversation between the nervous, immune and hormonal systems. These findings open up new approaches for managing conditions like diabetes, obesity, and cancer.
โFor decades, immunology has been dominated by a focus on immunity and infectionโ, says Henrique Veiga-Fernandes, head of the Immunophysiology Lab at the Champalimaud Foundation. โBut weโre starting to realise the immune system does a lot more than thatโ.
Glucose, a simple sugar, is the primary fuel for our brains and muscles. Maintaining stable blood sugar levels is crucial for our survival, especially during fasting or prolonged physical activity when energy demands are high and food intake is low.
Traditionally, blood sugar regulation has been attributed to the hormones insulin and glucagon, both produced by the pancreas. Insulin lowers blood glucose by promoting its uptake into cells, while glucagon raises it by signalling the liver to release glucose from stored sources.
Veiga-Fernandes and his team suspected there was more to the story. โFor exampleโ, he notes, โsome immune cells regulate how the body absorbs fat from food, and weโve recently shown that brain-immune interactions help control fat metabolism and obesity. This got us thinkingโcould the nervous and immune systems collaborate to regulate other key processes, like blood sugar levels?โ.
A New Circuit Uncovered
To explore this idea, the researchers conducted experiments in mice. They used genetically engineered mice lacking specific immune cells to observe their effects on blood sugar levels.
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They discovered that mice missing a type of immune cell called ILC2 couldnโt produce enough glucagonโthe hormone that raises blood sugarโand their glucose levels dropped too low. โWhen we transplanted ILC2s into these deficient mice, their blood sugar returned to normal, confirming the role of these immune cells in stabilising glucose when energy is scarceโ, explains Veiga-Fernandes.
Realising that the immune system could affect a hormone as vital as glucagon, the team knew they were onto something of major impact. But it left them asking: how exactly does this process work? The answer took them in a very unexpected direction.
โWe thought this was all being regulated in the liver because thatโs where glucagon exerts its functionโ, recalls Veiga-Fernandes. โBut our data kept telling us that everything of importance was happening between the intestine and the pancreasโ.
Using advanced cell-tagging methods, the team labelled ILC2 cells in the gut, giving them a glow-in-the-dark marker. After fasting, they found these cells had travelled to the pancreas. โOne of the biggest surprises was finding that the immune system stimulates the production of the hormone glucagon by sending immune cells on a journey across different organsโ.
Once in the pancreas, those immune cells release cytokinesโtiny chemical messengersโthat instruct pancreatic cells to produce the hormone glucagon. The increase in glucagon then signals the liver to release glucose. โWhen we blocked these cytokines, glucagon levels dropped, proving they are essential for maintaining blood sugar levelsโ.
โWhatโs remarkable here is that weโre seeing mass migration of immune cells between the intestine and pancreas, even in the absence of infection,โ he adds. โThis shows that immune cells arenโt just battle-hardened soldiers fighting off threatsโthey also act like emergency responders, stepping in to deliver critical energy supplies and maintain stability in times of needโ.
It turns out this migration is orchestrated by the nervous system. During fasting, neurons in the gut connected to the brain release chemical signals that bind to immune cells, telling them to leave the intestine and go to a new โpostcodeโ in the pancreas, within a few hours. The study showed that these nerve signals change the activity of immune cells, suppressing genes that anchor them in the intestine and enabling them to move to where theyโre needed.
Implications for Fasting and Exercise
โThis is the first evidence of a complex neuroimmune-hormonal circuitโ, Veiga-Fernandes observes. โIt shows how the nervous, immune, and hormonal systems work together to enable one of the bodyโs most essential processesโproducing glucose when energy is scarceโ.
โMice share many fundamental biological systems with humans, suggesting this inter-organ dialogue also occurs in humans when fasting or exercising. By understanding the role of ILC2s and their regulation by the nervous system, we can better appreciate how these daily life activities support metabolic health. Weโre eavesdropping on conversations between organs that weโve never heard beforeโ.
He adds that the immune system likely evolved as a safeguard during adversity, pointing out that our ancestors didnโt have the luxury of three meals a day and, if they were lucky, might have managed just one. This evolutionary pressure would have pressured our bodies to find ways to ensure that every cell gets the energy it needs.
โWeโve long known that the brain can directly signal the pancreas to release hormones quickly, but our work shows it can also indirectly boost glucagon production via immune cells, making the body better equipped to handle fasting and intense physical activity efficientlyโ.
Cancer, Diabetes and Beyond
The findings could open new doors for managing a range of conditions, notably for cancer research. Pancreatic neuroendocrine tumours and liver cancer can hijack the bodyโs metabolic processes, using glucagon to increase glucose production and fuel their growth. In advanced liver cancer, this process can lead to cancer-related cachexia, a condition marked by severe weight and muscle loss. Understanding these mechanisms could help develop better treatments.
โBalancing blood sugar is also critical, not only for preventing obesity, but also for addressing the global diabetes epidemic, which affects hundreds of millions of peopleโ, remarks Veiga-Fernandes. โTargeting these neuro-immune pathways could offer a new approach to prevention and treatmentโ.
โThis study reveals a level of communication between body systems that weโre only beginning to graspโ, he concludes. โWe want to understand how this inter-organ communication worksโor doesnโtโin people with cancer, chronic inflammation, high stress, or obesity. Ultimately, we aim to harness these results to improve therapies for hormonal and metabolic disordersโ.
IMAGE CREDIT: Immunophysiology Lab, Champalimaud Foundation
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