Individuals with major depressive disorder or post-traumatic stress disorder have elevated levels of proteins linked to immune activity and inflammation called cytokines. It hasn’t been clear, however, whether depression increases cytokine levels, or if the cytokines themselves contribute to depression.

Figuring out the cytokine-depression link would be difficult to do in human subjects. However, depression can be induced in lab animals that have been exposed to repeated social stresses. Now, researchers have used this approach to reveal that elevated cytokine levels can be used to predict an animal’s susceptibility to depression.

In this study, researchers subjected mice to repeated social defeats by putting them in a cage with larger, more aggressive mice for short periods over a 10 day span. Each defeat event lasted only 5-10 minutes; however, the mice were also exposed to continued psychological stress by placing the aggressive mouse on the other side of a clear divider 24 hours a day. To make things worse, each day, a new aggressor was chosen. This protocol has previously been demonstrated to induce depression-like social avoidance behaviors in mice.

Mice were subjected to chronic stress using the same protocol multiple times over a longer time period (21 days). Researchers also subjected mice to purely emotional stress by forcing them to watch another mouse face a larger, more aggressive mouse through a clear divider.

From these studies, the only cytokine found to be elevated in mice that were later found to be susceptible to depression and anxiety was Interleukin-6 (IL-6). After exposure to chronic stress, IL-6 levels remained elevated for a month. Just witnessing a stressful situation also raised levels of IL-6 compared to the controls.

Depression has been associated with a genetic predisposition for many years. So in the new work, the researchers were interested in determining if immune differences in mice prior to stresses could act as a marker of this predisposition, predicting the development of depression. Blood samples were taken from mice before and after exposure to a social defeat stress. Prior to the social stress, mice that were more susceptible to depression had higher levels of leukocytes, specifically monocytes, a type of white blood cell. They also had modestly higher levels of T cells. These studies suggest a pre-existing susceptibility may correlate with differences in an individuals’ immune activity.

To investigate the relationship between increased immune activation and stress, researchers isolated the precursors of immune cells: bone marrow (BM) hematopoietic progenitor cells. Cells from susceptible mice with high IL-6 levels and cells from control mice that lacked IL-6 were transplanted into separate animals. Overall, stress-susceptible BM chimeras had more circulating leukocytes than the control chimeras.

These mice were subjected to a low stress level that would not induce social avoidance in normal mice: three consecutive 5-min defeat sessions with 15 minute breaks in between. Mice were assessed for social avoidance behaviors 24 hours after the final session. Mice with stress-susceptible bone marrow showed increased social avoidance when subjected to low social stress situations. Even when exposed to a low level of emotional stress by watching aggressive interactions, these mice showed greater social avoidance behavior.

What happened to the mice that received bone marrow cells that had been genetically engineered to lack IL-6? These mice, and the original mice that the bone marrow was obtained from, were exposed to 10 days of repeated social defeat stress. Both types of mice showed similar levels of resilience, so perhaps leukocyte derived IL-6 is critical in the development of social avoidance.

These studies suggest that preexisting individual differences in immune system can predict and promote stress susceptibility. Although preliminary, these results may be clinically relevant. Patients with treatment-resistant major depressive disorder also had higher IL-6 levels than controls. In patients taking standard anti-depressants, the treatment did not lower circulating levels of IL-6. This suggests that standard anti-depressants are not acting on immune function; should IL-6 prove to be a major contributor to the disorder, it leaves the door open to treatments targeting immune function.

PNAS, 2014. DOI: 10.1073/pnas.1415191111 (About DOIs).