Neuroimmune and neuroendocrine abnormalities in depression - Horowitz & Zunszain - 2016 - Article

What are the results of chronic stress and depression?

As a result of chronic stress, we develop endocrine and immunological abnormalities, which increases the chance of illness, such as depression. Specifically, the hypothalamic-pituitary-adrenal (HPA) axis (endocrine system) and proinflammatory cytokine network (immune system) become dysfunctional. These changes are related to depression as they can lead to a dysfunctional monoamine system, impaired neurogenesis, abnormal regional brain activity and changes in synaptic functioning.

What is the glucocorticoid theory?

When stressed, cortisol is released by the HPA axis to respond adaptively to threat. When stress is chronic both steady-state and dynamic responses of the HPA axis become abnormal, which is also common in depression. Often the glucocorticoid receptor (GR) is impaired in depression. The GR gives feedback to the HPA axis, but when it is impaired it leads to glucocorticoid resistance. According to the glucocorticoid theory, chronic stress leads to extremely high HPA axis activity increasing the cortisol production massively.

What is the cytokine theory?

Chronic stress and depression cause the immune system to function abnormally. Proinflammatory cytokines are produced, which leads to neurological changes, such as the abovementioned dysfunctional monoamine system and impaired neurogenesis. It is important to integrate the glucocorticoid and cytokine theory when researching depression.

What is the relation between the HPA axis and immune system?

The immune system influences the HPA axis as proinflammatory cytokines lead to corticotropin-releasing hormone (CRH) and adrenocorticotropin (ACTH) release and GR resistance. The HPA axis influences the immune system by stopping transcriptional activity of an inflammatory transcription factor and inhibiting production and release of proinflammatory cytokines. The question arises how both systems can then be overactive at the same time. Two theories are suggested below.

What is the glucocorticoid resistance hypothesis?

This hypothesis suggests that depressed individuals have less glucocorticoid action, because glucocorticoid resistance causes less signal transfers for each cortisol molecule. Therefore, the immune system is less inhibited by glucocorticoid action and can increase its signalling leading to more proinflammatory cytokines. However, under normal conditions, glucocorticoids protect individuals from excessive inflammatory reactions by suppressing the production and secretion of cytokines.

What is the evidence for the glucocorticoid resistance hypothesis?

Research has found that individuals with chronic stress have increased immune action compared to glucocorticoid action. They not only have increased glucocorticoid resistance, but also higher levels of proinflammatory cytokines, which makes them vulnerable to develop illnesses. Similar results have been found in individuals with depression. However, we need a more sensitive and specific measure for glucocorticoid resistance.

Do glucocorticoids have proinflammatory effects?

Another hypothesis is that glucocorticoids can be pro and anti-inflammatory under different conditions. Glucocorticoid action preceding an inflammatory insult could be proinflammatory, while glucocorticoid action at the same time or after an insult could be anti-inflammatory. This is consistent with the evolutionary idea that the immune system is supressed during acute threat and glucocorticoid levels are increased for a fight or flight response. In the recovery period glucocorticoid levels and immune function normalise. Increased glucocorticoid action is seen as a warning signal. In response to inflammation microglia produce proinflammatory cytokines, which is inhibited by glucocorticoid action.

What Is the evidence for the proinflammatory effects of glucocorticoids?

The inflammatory response is inhibited when individuals are exposed to stress after an inflammatory insult. When exposed to stress before the insult, the inflammatory response is enhanced. However, glucocorticoids should not be administered too soon before the insult, as this could cause anti-inflammatory reactions. The pro-inflammatory effects of glucocorticoids come about by enhancing the expression of cytokine receptors in immune cells in the periphery. Additionally, some anti-inflammatory pathways are downregulated. However, the proinflammatory effects have only been demonstrated in animals and peripheral human cells. Research should focus on the human brain and central cells. This is challenging as methods are invasive (cerebrospinal fluid sampling) or lack temporal resolution (positron emission tomography). Also, research should be expanded to larger time frames, as changes in depression persist for weeks or months.

Are there different relations between the immune system and the HPA axis?

The immune system and the HPA axis are also indirectly related. Glucocorticoids affect brain regions responsible for adrenergic activity, which in turn affects the inflammatory responses. Furthermore, there appears to be a vicious cycle as proinflammatory cytokines on the one hand lead to the secretion of CRH, ACTH and cortisol, but glucocorticoids on the other hand have proinflammatory effects. It is unclear what mechanism leads to the steady-state. Perhaps there is a third unrelated mechanism which influences both the HPA axis and the immune system.

What are future directions?

Future studies should examine the effect of glucocorticoid resistance on the proinflammatory characteristics of glucocorticoids or vice versa. Currently this is being studied by using human hippocampal progenitor cells. These cells increase proinflammatory cytokine levels greatly when exposed to an inflammatory stimulus. Preliminary findings show that glucocorticoid treatment of the hippocampal cells enhanced the inflammatory responses if administered before an inflammatory insult. Inflammatory responses were less enhanced, when glucocorticoids were administered together with a GR antagonist.