Interleukin-6 is Important for the Induction of Stress-Induced Anxiety

Post by: Amanda McFarlan

What's the science?

Interleukin-6 is part of a group of small molecules, known as cytokines, that are important for cell signaling in the immune system. Studies have shown that elevated levels of interleukin-6 are consistently found in individuals suffering from mood disorders like depression and anxiety. Still, the functional role of interleukin-6 in mediating the development and progression of these disorders is not well understood. This week in Biological Psychiatry, Niraula and colleagues aimed to examine interleukin-6 in the peripheral immune response to determine its role in stress-induced anxiety.

How did they do it?

The authors used two types of mice, wildtype (i.e. normal) and interleukin-6 knockout (i.e. interleukin-6 gene made inoperative), to study the role of interleukin-6 in stress-induced anxiety and social avoidance behaviour. To induce stress in mice, they used a method called repeated social defeat whereby one aggressive mouse was brought into a cage of 3 established mice for 2 hours/day for 6 consecutive days. The aggressive interactions result in defeat-induced subordination. There were four groups of mice: wildtype-stress, wildtype-control, interleukin-6-knockout-stress and interleukin-6-knockout-control. Fourteen hours following the last stress-inducing cycle, all four groups of mice were tested for anxiety-like behaviours using open field and social avoidance tasks. In addition to the behavioural testing, bone marrow, blood samples and brain samples were collected fourteen hours after the last stress-inducing cycle. These samples were used to detect and quantify the presence of interlueukin-6 as well as other inflammatory markers using techniques like flow cytometry, ELISA, real-time qPCR, and nanoString RNA analysis.

What did they find?

The authors found that wildtype mice in the stress condition, compared to both interleukin-6-knockout mice in the stress condition and controls, made fewer entries and spent less time in the center of the open field — indicating anxiety-like behaviours. They also found that wildtype mice in the stress condition spent the largest amount of time in a corner (away from social interaction) and less time in the interaction zone (where they  socially interact with other mice) in the social avoidance task compared to interleukin-6-knockout mice in the stress condition and both control groups. These findings suggest that interleukin-6 knockout mice were protected against stress-induced anxiety and social avoidance behaviours observed in wildtype mice, implicating interleukin-6 as a potential mediator of stress. Analyses of brain and blood samples showed evidence of microglia activation and bone marrow-derived, primed monocyte (white blood cell) recruitment in the brain in both wildtype and interleukin-6 knockout mice. Recruitment of these cells usually leads to the expression of a cytokine known as interleukin-1-beta, that is important for the induction of anxiety-like behaviours. Elevated levels of interleukin-1-beta were observed in wildtype, but not in interleukin-6-knockout mice in the stress condition, suggesting that interleukin-6-knockout mice are protected from the induction of interleukin-1-beta in response to stress. Lastly, analysis of monocyte RNA (using nCounter Nanostring analysis) revealed that exposure to stress caused changes in immune-related gene expression that was interleukin-6 dependent. Specifically, monocytes released from the bone marrow had a primed phenotype that was different from the normal homeostatic monocytes released throughout the day and showed increased expression of receptors for cytokines and adhesion molecules. They were also insensitive to glucocorticoid regulation of proinflammatory cytokines. 


What's the impact?

This is the first study to show that inflammatory monocytes travel to the brain in response to stress, and are critical for inducing anxiety. The authors show that stress-induced increases in interleukin-6 circulation pushes monocytes towards an inflammatory profile, causing increased interleukin-1 in the brain and consequently, anxiety. These findings are important for understanding the role of the immune system in mood disorders and may provide insight into the development of new therapeutics for these disorders.  


 Niraula et al. IL-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes that Facilitate Anxiety. Biological Psychiatry (2018). Access to the original scientific publication here.