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Getting warmer: thermoregulation and inflammation

The human body has a number of innate responses to infection that include heating the affected part of the body, or cooling it down. Yale School of Medicine researchers are looking hard at the causes behind both.

The body survives infection in one of two ways: resistance or tolerance. In resistance, the body uses its resources to mount an all-out war against the invading threat and eliminate it. In tolerance, rather than spending its resources on an attack, the body downshifts into “power-saver” mode where it rides out the infection.

During this time, trade-offs are made. Appetite loss in sickness, for example, allows the body to turn its energy away from food metabolism and conserve strength for weathering the illness ahead. And body temperature regulation, researchers are learning, may also be a key trade-off when surviving an infection is the body’s top priority.

“The idea of using temperature to modulate metabolism and affect immunity is not new, it’s just not understood,” said Andrew Wang, MD, PhD, HS ’13, FW ’17, assistant professor of medicine (rheumatology) and of immunobiology.

Ancient Egyptians used cryotherapy to treat inflammation as early as 2500 BCE. The Edwin Smith Papyrus, the oldest known medical text, dated 3500 BCE, mentions cold therapy multiple times.

More recent research has begun to disassemble the mechanism behind thermoregulation’s immunological success. “It turns out we have to spend a considerable amount of energy defending our body temperature,” said Wang. Saving that energy could help the body enter tolerance mode.

In a study published in Cell in 2019, Wang and his colleagues examined a hormone (growth differentiation factor 15 or GDF15) that further illuminates the role of metabolic regulation in infection tolerance. In mouse models of both bacterial and viral sepsis, GDF15 was crucial for survival—which suggested its value isn’t measured by helping the immune system attack a specific type of invader. In fact, the hormone is triggered after the body launches an inflammatory response. The hormone didn’t reduce pathogen levels in mice compared to those in which GDF15 was blocked, either.

Researchers suspected that the hormone doesn’t help the body resist infection at all. Rather, it helps the body tolerate the inflammation that is necessary to fight it.

“In an overwhelming infection like sepsis, where inflammation becomes a big problem, the tolerance approach—rather than resistance —can be beneficial,” said Ellen Foxman, MD, PhD, FW ’15, assistant professor of laboratory medicine and immunobiology.

The researchers identified physiological changes that seemed to shift the mice into tolerance mode. For one, GDF15 protected the heart from injury in sepsis. It also maintained the body’s temperature. Mice in which the hormone was blocked suffered hypothermia—a serious problem in sepsis patients.

According to Wang, it will be very important to understand how metabolism is controlled to increase resistance to disease. Cryopreservation and other states of suspended animation are extreme examples of “power saver” modes that confer maximal tolerance to inflammatory insults. “Animals that hibernate are extraordinarily resistant to stress, trauma, infection, and most inflammatory injuries,” said Wang. “There’s tremendous interest in seeing how that works.”