The neurotransmitter norepinephrine, which plays a key role in the fight-or-flight stress response, alters immune responses by inhibiting the movement of various white blood cells in different tissues, the researchers report on April 28 in the journal. Immunity. The rapid and transient effect has occurred in mice with infections and cancer, but as of yet, it is not known whether the results generalize to humans with various health conditions.
“We found that stress could prevent immune cells from moving and prevent immune cells from protecting against disease,” says Scott Mueller (@SMuellerLab) of the Peter Doherty Institute for Infection and Immunity (Doherty Institute), lead author of the study at the University of Melbourne. “This is new because it was not known that stress signals can prevent immune cells from moving around the body and doing their jobs.”
A primary function of the sympathetic nervous system (SNS) is to coordinate the fight-or-flight stress response – a group of changes that prepare the body to fight or flee in stressful or dangerous situations to protect itself against d ‘possible damage. Most tissues, including lymph nodes and the spleen, are innervated by SNS fibers. Stress-induced activation of SNS may suppress immune responses, but the underlying mechanisms have been poorly characterized. “We hypothesized that SNS signals could alter the movement of T cells in tissue and lead to compromised immunity,” Mueller says.
White blood cells, also known as leukocytes, are constantly traveling throughout the body and are highly mobile in tissues, where they locate and eradicate pathogens and tumors. Although the movement of leukocytes is critical for immunity, it has not been clear how these cells integrate various signals to navigate tissues. “We also hypothesized that neurotransmitter signals could be a rapid way to modulate the behavior of leukocytes in tissue, particularly during acute stress that involves increased activation of the SNS,” says Mueller.
To test this idea, the researchers used advanced imaging to track the movement of T cells in the lymph nodes of mice. Within minutes of being exposed to norepinephrine, the rapidly moving T cells stopped and retracted their arm-shaped protrusions. This effect was transient, lasting between 45 and 60 minutes. Localized administration of norepinephrine into the lymph nodes of living mice also rapidly shut down the cells. Similar effects were seen in mice given infusions of norepinephrine, which is used to treat patients with septic shock – a life-threatening condition that occurs when infection causes dangerously low blood pressure. This finding suggests that therapeutic treatment with norepinephrine may alter leukocyte function.
“We were very surprised that stress signals had such a rapid and dramatic effect on the way immune cells move,” says Mueller. “Since movement is at the heart of how immune cells can reach the right parts of the body and fight infections or tumors, this fast-moving switch was unexpected.”
Further experiments revealed that SNS signals inhibit the migration of distinct immune cells, including B cells and dendritic cells, exerting these effects in different tissues such as skin and liver. Additional results suggest that the effects of SNS activation on cell motility may be mediated by constriction of blood vessels, reduction in blood flow, and oxygen deprivation in tissues, resulting in increased calcium signaling. in leukocytes.
“Our results reveal that an unintended consequence of modulating blood flow in response to SNS activity is the rapid detection of oxygen changes by leukocytes and inhibition of motility,” says Mueller. “Such rapid paralysis of leukocyte behavior identifies a physiological consequence of SNS activity which explains, at least in part, the widely observed relationship between stress and impaired immunity.”
Additionally, SNS signals impaired protective immunity against pathogens and tumors in various mouse models, decreasing proliferation and expansion of T cells in lymph nodes and spleen. For example, treatment with SNS-stimulating molecules rapidly stopped the movement of T cells and dendritic cells in mice infected with herpes simplex 1 virus and reduced the recruitment of virus-specific T cells to the site of skin infection. Similar effects were seen in mice with melanoma and in mice infected with a malaria parasite.
“Our data suggest that SNS activity in tissue could impact immune outcomes in various diseases,” says Mueller. “A better understanding of the impact of adrenergic receptor signals on cellular functions in tissues may inform the development of improved treatments for infections and cancer.”
The extent to which SNS activation affects leukocyte behavior or disease outcomes in humans remains to be determined. In particular, the increase in SNS activity is important in patients with obesity and heart failure, while psychological stress can cause constriction of blood vessels in patients with heart disease. An unappreciated impact of increased SNS activity, especially in people with underlying health conditions, could be impaired behavior and function of white blood cells. The findings may also have important health implications for patients who use SNS-activating drugs to treat conditions such as heart failure, sepsis, asthma, and allergic reactions.
In the future, researchers will examine in more detail the mechanisms by which immune cells are affected by SNS stress signals and explore relevant strategies for stimulating anti-cancer responses in patients. “This knowledge will allow us to test the impact of drugs that block the sympathetic stress pathway, such as beta blockers, on the outcome of vaccination and cancer treatments,” says Mueller. “These types of drugs could be safe treatment options for patients where stress could contribute to poor immune function.”
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