The Immune System's Link With Stress & Depression
There has always existed a strong link between high levels of stress and the onset of depression. A recent study out of the Icahn School of Medicine at Mount Sinai and published October 20 in the Proceedings of the National Academy of Sciences (PNAS) has shown some of us may be at greater risk than others for developing stress-related depression or anxiety due to inherent differences in our immune system.
Our immune system triggers an inflammatory response when exposed to infection or disease, and the effects of stress on this response have also been well documented. When we experience a bout of depression or anxiety, our body responds by increasing its levels of inflammatory molecules and white blood cells. The grey area in all of this science was whether or not there was already an increased amount of inflammation present prior to the diagnosis of the disease or whether the depression triggered the response.
The Beginning of the Study
By closely examining the peripheral immune system, researchers at Mount Sinai isolated a specific set of structures and processes in the lymph nodes and other tissues that work to fight off disease. When over stressed, it is known that our body responds through a complex inflammatory cascade. When triggered (by a virus, for example), inflammatory proteins, called interleukins, are released by our white blood cells in an attempt to decrease infection, reduce further damage, etc. It is possible, however, for the inflammatory process to become over-reactive and hypersensitive to an attack, and ultimately, over time, the inflammatory system stops working correctly and can actually cause disease. Using a social stress model in mice, researchers uncovered preexisting differences in the sensitivity of the peripheral immune system that they state can predict and promote vulnerability to social stress.
In this study, researchers exposed mice to social stress models that can be translated to similar social stressors in humans. To simulate stress, they exposed non-aggressive mice to an aggressive mouse for 10 minutes a day for 10 days. They were able to observe repeated social defeat stress consistently over the course of those 10 days. This is a purely emotional stressor, and can be likened to bullying behavior and it’s effects in humans. Non-aggressive mice were labeled “susceptible” due to the fact they preferentially selected to relocate near an empty cage as opposed to engaging with a new mouse in subsequent social interaction tests. Mice considered “resilient” demonstrated an opposite profile. The susceptible mice exhibited clear social avoidance that arose from repeated exposure to social subordination. Such avoidance leads to depression.
Investigators took cytokine profiles of the mice 20 minutes after the first social stress exposure. Interleukin-6 (IL6), one of the cytokines regulated by stress, was the most elevated in susceptible mice compared with resilient mice. They also found the levels of leukocytes (white blood cells that release IL-6) were higher in stress susceptible mice before stress exposure. Researchers also uncovered a similar elevation of serum IL-6 in two separate groups of human patients with treatment-resistant Major Depressive Disorder (MDD), establishing a human link to this study and it’s outcomes. This evidence is the first to suggest that IL6 response prior to social stress exposure can predict individual differences in vulnerability to a subsequent social stressor.
"Interleukin-6 could be a risk factor for the development of depression in vulnerable individuals," says Dr. Scott Russo, PhD, Associate Professor of Neuroscience and leader of the trial. "We believe our studies could have significant impact on the development of new antidepressant therapeutics that inhibit IL-6, which may reduce stress-induced relapse in patients with major depressive disorder." Further, "Our data suggests that pre-existing individual differences in the peripheral immune system predict and promote stress susceptibility," says lead author Georgia Hodes, PhD, Postdoctoral Researcher in Neuroscience. "Additionally, we found that when mice were given bone marrow transplants of stem cells that produce leukocytes lacking IL-6 or when injected with antibodies that block IL-6 prior to stress exposure, the development of social avoidance was reduced compared with their respective control groups, demonstrating that the emotional response to stress can be generated or blocked in the periphery."
It’s worth noting that by replacing a non-stressed mouse’s peripheral immune system with that of a stressed one, their susceptibility to social stress increased and the mouse demonstrated defeated behaviors. Also, by depleting the cytokine IL-6 from the whole body or just from leukocytes, or sequestering IL-6 outside of the brain increased resiliency.
These studies show real insight into and promise for new and successful treatments in the area of depression, particularly Repeated Social Defeat Stress. If researchers can generate or block the stress response in the peripheral nervous system, the door is opened for new treatment opportunities in the area of stress disorders. Down the road, scientists may even be able to reduce an individual’s vulnerability to stress, and subvert potential related depression by focusing on and reengineering the patient’s immune system.
Conclusion: Artificially increasing IL-6 levels in the peripheral nervous system of self-isolating and depressive mice mice may enhance their resilience and social engagement.
- Laura Wells
Bruce, M. (Ed.). (2014, September 25). Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Retrieved November 19, 2014, from http://www.pnas.org/content/111/45/16136
Mount Sinai Medical Center. (2014, October 20). Stress-related inflammation may increase risk for depression. ScienceDaily. Retrieved November 19, 2014 from www.sciencedaily.com/releases/2014/10/141020212341.htm
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