Cytokines, small proteins released by cells throughout the body, are generally known as chemical messengers that play a critical role in controlling inflammatory and immune responses. Growing evidence suggests, however, that cytokines also contribute to neuropathology, including disease effects on brain signaling and neural circuit behavior.
Among the different types of cytokines (interleukins, interferons, and chemokines, among others), researchers have found that one class—proinflammatory cytokines—are involved in what is known as the “sickness response.”
Immune System and Brain
The sickness response is a nonspecific immune reaction that triggers a series of physiological and behavioral changes, including fever, eating and drinking less, decreased social interaction, and increased anxiety. It also activates the body’s stress response. Triggered by signals in the brain’s hypothalamus, the sickness response is the body’s attempt to produce energy to fight infection as well as preserve energy through behavior changes.
Scientists have found that macrophages, cells that protect the body against infection, create proinflammatory cytokines including interleukin-1, interleukin-6, and tumor necrosis factor. These work inside the brain to activate the sickness response.
“This name [proinflammatory cytokines] reflects the fact that these proteins orchestrate and augment inflammatory responses,” says Linda R. Watkins of the Center for Neuroscience at the University of Colorado at Boulder. Preventing their actions blocks sickness, whereas administering them can lead to a sickness response, she adds.
Watkins and her colleague at the University of Colorado, Steven Maier, found that cytokines produced in the blood by macrophages (a type of white blood cell that helps to destroy bacteria) are not what tell your brain that you are sick, primarily because they are too large to pass through the blood-brain barrier, the tight layer of cells and tissue that normally keeps immune cells from entering the brain. Rather, the cytokines’ message passes through the vagus nerve to the brain.
Along the vagus nerve, which extends from the brainstem to the abdomen, sit small pockets of cells called paraganglia that secrete neurotransmitters. The paraganglia have receptors for interleukin-1 (IL-1), one of the proinflammatory cytokines released by macrophages.
Maier first described the immune-to-brain circuit that regulates the sickness response in 2001. A macrophage releases IL-1, which binds to paraganglia along the vagus nerve, he said. Neurotransmitters in the paraganglia then activate the vagus nerve, sending the signal to the brain. This signal in turn tells the brain to make its own IL-1, which sets off the sickness response and sends the signal back to the immune system.