Magnified IL-6 Response Linked To Stress Susceptibility and Higher Risk of Depression

Magnified IL-6 response Stress Risk Depression
Magnified IL-6 Response – Stress Susceptibility – Risk of Depression

Update at BrainImmuneA new study published in the Proceedings of the National Academy of Sciences of the USA is perhaps the first to demonstrate that the magnitude of peripheral interleukin (IL)-6 responses preceding stress challenge may confer inter-individual differences in susceptibility or resilience to a subsequent social stressor.

Previous research indicates that in humans both major depression and psychological stress, under certain conditions, are related to increased systemic concentrations of the pro-inflammatory cytokine IL-6 (Maes M, et al., Cytokine, 1997, 11:853; Alesci S, et al., J Clin Endocrinol Metab. 2005, 90:2522). It is not known, however, whether high IL-6 response actually precedes the onset of depression or, alternatively, is the result of the disorder.

In this study, Georgia Hodes et al., as part of an international research team from the US, UK and the Netherlands have used two stress models – social defeat stress (RSDS) and witness defeat stress. Similarly to data in humans, they observed that in mice chronic social subordinations induced a depression-like behavior, such as social avoidance, in a subgroup of mice termed susceptible, whereas resilient mice resisted the development of such behavior.

Measuring cytokine levels after the first exposure to an aggressor in the RSDS model, the authors found that susceptible mice had about a 9-fold increase in IL-6 levels as compared to resilient mice. These results appear clinically relevant and related to other stress paradigms as the authors detected higher IL-6 levels in both humans with treatment-resistant major depressive disorder and mice with chronic variable stress.

The researchers also reported that several days before the experiments and the stress challenge, mice that later developed the susceptible phenotype had increased number of leukocytes (and specifically monocytes), and that these cells released more IL-6 in response to immune challenge. According to the authors this suggests the presence of preexisting individual differences in immune reactivity before RSDS.

The authors conclude that individual differences in the sensitivity of some peripheral immune cells, and more specifically, their IL-6 hyper-responsiveness are preexisting and may determine a greater risk of developing a stress-related disorder, such as depression in a subgroup of susceptible individuals.

Source: Proc Natl Acad Sci U S A. 2014 Oct 20. pii: 201415191. [Epub ahead of print]
Read more: PubMed


A 2017 study indicates and as we recently reported the appearance of depressive symptoms in inflammatory conditions might be primarily linked to an increase in central IL-6 concentration. In this study Harald Engler and Manfred Schedlowski from the Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, Germany, demonstrated that IL-6 might be one of the key messengers transferring the inflammatory signal from the periphery to the brain.

They found that in healthy male volunteers that intravenous administration of low-dose endotoxin induced a vigorous increase of IL-6 in the cerebrospinal fluid (CSF). This study suggests that the appearance of depressive symptoms in inflammatory conditions might be primarily linked to an increase in central IL-6 concentration.

A 2020 study determined the IL-6-related immune response, neuroinflammation, and anxiety following repeated social defeat (RSD) stress in mice. Specifically, it studied the role of IL-6 in the monocyte-mediated response to stress and the development of anxiety.

The role of inflammatory cytokines in the development and progression of psychiatric illnesses is significant. For example, patients with mood disorders nonresponsive to selective serotonin reuptake inhibitors (SSRIs) showed significantly higher levels of peripheral IL-6. High levels of CRP and IL-6 were also reported in individuals with anxiety disorders.

The same authors have shown previously that circulating monocytes recruited to the brain during stress relay an IL-1β signal to the brain, augmenting the neuroinflammatory profile and subsequently inducing anxiety-like behavior in mice.

Here, they show that IL-6 plays a role in two key responses to stress: behavior and brain IL-1β expression, and support the notion that IL-6 is a critical mediator of anxiety-like behavior and social avoidance following social defeat.

The authors provide novel evidence that IL-6 directly and robustly alters the profile of monocytes released from the bone marrow in response to social defeat stress. This primed signature of peripheral monocytes took on an IL-6-dependent inflammatory/reactive profile following recruitment to the brain. Thus, IL-6 produced during stress is critical to the generation of primed and pro-inflammatory monocytes that trigger the development of anxiety-like behavior.

In conclusion, the authors show that IL-6 is vital to the priming of bone marrow-derived peripheral monocytes that are recruited to the brain during repeated social defeat and trigger anxiety-like behavior. Thus, IL-6 production during RSD primes peripheral monocytes that traffic to the brain and augment IL-1β signaling that is associated with anxiety-like behavior.

Cover Image Credit: Link between Cerebrospinal Fluid IL-6 and Depressive Symptoms
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