Stress 'paralyzes' white blood cells and severely impairs immune response in mice

April 28, 2021
This image shows lymphocytes (purple) among blood vessels (orange), and the calcium signalling (green) that results from noradrenaline neurotransmitter release and causes immune cells to stop moving. (Scott Mueller)

This image shows lymphocytes (purple) among blood vessels (orange), and the calcium signalling (green) that results from noradrenaline neurotransmitter release and causes immune cells to stop moving. (Scott Mueller)

In a finding that could have key implications for cancer and viral infections in human patients, Australian researchers induced sickness in mice and then stressed them out, showing for the first time that the rodents' white blood cells effectively lost the ability to move, potentially leading to a slowed immune response and an increased vulnerability to further infection.

A group of Australian scientists interested in how stress impacts the immune system used advanced laser microscopes to track the activity of immune cells in mice and observe interactions between the nervous system and immune system, as detailed in a paper published Wednesday in Immunity

"Stress is known to have negative effects on the immune system. Anecdotally, when we are stressed, we are more likely to get sick, and we wanted to know more about why this can occur," Scott N. Mueller, a professor at the University of Melbourne and the senior author of the paper, told The Academic Times. "We postulated that signals from the nervous system, known as neurotransmitters, in particular adrenaline and noradrenaline produced by the sympathetic nervous system in response to stress, could impair how immune cells function."

The sympathetic nervous system, a part of the body's autonomic nervous system that controls biological processes such as heart rate and blood flow, is frequently associated with weakened immunity when it is activated in response to psychological or physical stress. To study this process, the researchers treated mice with neurotransmitters and adrenergic-receptor drugs, which are medications that stimulate the stress response. "We also used advanced tools to directly activate the nerves in mice, thereby mimicking the natural activity of the nerves to follow the effects on the immune cells," Mueller added.

They used advanced imaging to track T cells, a type of white blood cell, in mouse lymph nodes, skin and liver. By contrast, tracking T cells is very difficult to do in human lymph nodes, Mueller said. But people with viral infections or cancer are often treated with the same drugs that were tested in the mice, such as noradrenaline, also known as norepinephrine, an organic chemical that functions in the body as a hormone and neurotransmitter and plays a key role in the fight-or-flight stress response.

The motility of white blood cells is critical for immunity, the authors said in the paper, but they found that within minutes of treating the mice with noradrenaline and stimulating their sympathetic nervous system, their white blood cells that had been rapidly moving stopped moving for up to an hour. And if the researchers continued this treatment, the cells remained stopped for much longer. This can impair the body's immune response and prevent it from protecting the body against disease. 

"We found that the signals produced by nerves in response to stress can paralyze immune cells," Mueller said, which suggests that any intense period of stress has the potential to stop immune cells from functioning properly and may impair immunity to different diseases.

"Our study is novel because it was not known that stress signals can stop immune cells from moving about in the body and functioning," Mueller explained. "We were very surprised that stress signals had such a rapid and dramatic effect on how immune cells move."

"We found that stress altered blood flow that was sensed by immune cells, making them stop," he continued. "Movement is fundamental to how immune cells do their job, and this rapid off switch was highly unexpected."

The authors had hypothesized that sympathetic nervous system signals might simply "modify" the movement of T cells and lead to compromised immunity, but the noradrenaline "triggered a swift loss of motility" in the mice T cells. Noradrenaline also decreased heart rate and increased blood pressure in the mice. The findings provide "a mechanistic understanding of the link between adrenergic receptors and compromised immunity," according to the paper.

Though this has not been confirmed in humans, the authors said in the paper that their results indicate that therapeutic treatment with noradrenaline in sick patients might be impairing their white blood cell functions. "Our research suggests that blocking these stress pathways using safe drugs such as beta blockers might improve immune responses," Mueller said. "These types of drugs might be safe treatment options for patients where stress could contribute to poor immune function."

The team behind the paper is currently studying how the sympathetic nervous system stress signals impair immune responses to cancer, Mueller said, and whether it is possible to block these pathways to improve treatment responses in cancer patients. "Future studies need to reveal the impact of these stress pathways on immune cells at the molecular level so that we can identify biomarkers of this stress response and have a more direct way to measure this," Mueller added. 

The study, "Adrenergic regulation of the vasculature impairs leukocyte interstitial migration and suppresses immune responses," published April 28 in the journal Immunity, was authored by Sapna Devi, Yannick O. Alexandre, Joon Keit Loi, Nazanin Ghazanfari, Lauren E. Holz, Laura K. Mackay, William R. Heath and Scott N. Mueller, the University of Melbourne; Ryan Gillis and David Shackleford, Monash University; Sarah J. Creed, Monash University and Hudson Institute of Medical Research; and Erica K. Sloan, Monash University and Peter MacCallum Cancer Center.

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