The HPA – Immune Axis in the Brain

The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain – free full-text /PMC3978367/ – Front Immunol. 2014;

In response to physiological and psychogenic stressors, the hypothalamic–pituitary–adrenal (HPA) axis orchestrates the systemic release of glucocorticoids (GCs).

By virtue of nearly ubiquitous expression of the GC receptor and the multifaceted metabolic, cardiovascular, cognitive, and immunologic functions of GCs, this system plays an essential role in the response to stress and restoration of an homeostatic state.

GCs act on almost all types of immune cells and were long recognized to perform salient immunosuppressive and anti-inflammatory functions through various genomic and non-genomic mechanisms.  

These renowned effects of the steroid hormone have been exploited in the clinic for the past 70 years and synthetic GC derivatives are commonly used for the therapy of various allergic, autoimmune, inflammatory, and hematological disorders.

The role of the HPA axis and GCs in restraining immune responses across the organism is however still debated in light of accumulating evidence suggesting that GCs can also have both permissive and stimulatory effects on the immune system under specific conditions.

While I’d never heard of this, it doesn’t surprise me. Very little in or about our bodies is on-off or “digital”.

To maintain the balance of our individual body chemistries (homeostasis), internal chemical processes are continuously adjusting the relative concentrations of various interdependent molecules.

These are often reciprocal: a high concentration of one molecule stimulates a certain desired reaction and a high concentration of the other spurs a counter-reaction. The trick is to keep both at a steady level even with everything else going on in our bodies (like screaming pain signals).

On a molecular level, our body is in a neverending process of stimulation and response, every adjustment inevitably leading to the next and the next somewhere else along the chemical process.

Such paradoxical actions of GCs are particularly evident in the brain, where substantial data support either a beneficial or detrimental role of the steroid hormone.

In this review, we examine the roles of GCs on the innate immune system with a particular focus on the CNS compartment.

We also dissect the numerous molecular mechanisms through which GCs exert their effects and discuss the various parameters influencing the paradoxical immunomodulatory functions of GCs in the brain.

In this case, don’t they actually mean “balanced”?

Almost everywhere in our bodies, both too much of or too little of any molecule/substance will be problematic. The desired state is usually a balance somewhere between the extremes which has to be nudged one way or the other depending on whether more or less is needed.

CNS Innate Immune System

Robust inflammatory responses are elicited in neuropathological contexts such as infection, traumatic injury as well as autoimmune and neurodegenerative disorders by the resident innate immune cells of the brain, microglia.

Dynamic research now aims at deciphering the crucial functions of microglia in preserving and restoring the brain homeostasis during immune challenges, injuries, and chronic diseases.

Microglia represent a heterogeneous cell population accounting for approximately 5–12% of total brain cells. They are distributed unevenly throughout the CNS

Microglial cells represent prime targets of GCs in the CNS owing to a predominant expression of GR.

Through these key innate immune cells, GCs therefore perform major regulatory functions on the innate immune system of the CNS in health and disease.

Context-Dependent Actions of the Glucocorticoid Receptor

A myriad of glucocorticoids receptor (GR), epigenetic, and contextual parameters underlie the cell-, signal-, and gene-specific actions of glucocorticoids (GCs).

GC actions on gene expression are thus first influenced by the relative abundance of the numerous GR isoforms in a given cell or tissue. In similar fashion, the differential expression of transcription factors, co-activators, co-repressors, and other binding partners are critical in tailoring the actions of GCs through the GR.

This is exactly the reciprocal action of maintaining a balance between too much and too little I referred to earlier.

The activation state of a target cell and the specific transduction signaling pathways triggered at a given time further define the actions of the GR. Signaling pathways can fine-tune GR activity through various post-translational modifications.

Paradoxical Actions of GCs on the Innate Immune System of the Brain

Whether GCs play beneficial or detrimental roles in the CNS in health and diseases have been debated for decades, and the complex dichotomous and context-dependent actions of the steroid hormone certainly add to the confusion.

The fact that GC actions evolve dynamically over time and the incomplete understanding of the parameters driving the CNS innate immune system toward tissue maintenance/repair or damage also warrant a careful interpretation of the literature. H

Here, we review experimental evidence supporting the bidirectional actions of GCs in the brain.

Anti-inflammatory actions of GCs in the brain

Substantial evidence established that GCs restrain and/or terminate the innate immune response in the CNS following either a peripheral or cerebral challenge.

GCs were also shown to prevent the production of pro-inflammatory mediatory in cultured microglia .

Glucocorticoids also exert salient anti-inflammatory actions when the immunogenic insult is taking place within the CNS compartment.

Pro-inflammatory actions of GCs in the brain

The vast majority of GC pro-inflammatory actions in vivo were described in animal models of acute or chronic stress. As a matter of act, both types of stress elicit an HPA response and were shown to exacerbate salient features of inflammation in the CNS provided that they occur prior to peripheral or cerebral immune insults.

Therefore, as for the anti-inflammatory actions of GCs, the activation state and signaling context of a target cell also define its pro-inflammatory functions.

Parameters determining the dichotomous roles of GCs in the CNS

Numerous parameters were found to influence the dichotomous actions of GCs. Of particular interest is the timing of GC exposure relative to an immune challenge. Prior work established that acute stress or exogenous GCs can potentiate or conversely repress the same pro-inflammatory genes provided that they are respectively administered before or after LPS.

Lipopolysaccharide (LPS) is a molecule that deliberately induces inflammation.

It should also be kept in mind that a pro-inflammatory environment does not automatically lead to collateral damages and that timing is again a key parameter here. While an exaggerated (magnitude or duration) inflammatory response can trigger neuronal injury and cell death, pro-inflammatory mediators may initially (i.e., acute phase) stimulate the clearance of debris, the recruitment of cellular reinforcements and program tissue remodeling.

Reading all these studies about inflammation, it’s easy to forget that it has a necessary and normal beneficial purpose as well.

Despite complicating the overall picture, such factors must be carefully considered when interpreting the actions of GCs in the CNS.

Conclusion

A wealth of experimental and clinical data provides clear evidence that accurate signaling between the nervous, endocrine, and immune systems leading to a proper feedback (timing, amplitude, duration, sensitivity, etc.) by GCs is mandatory to avoid serious detrimental consequences for the brain elements following an immunogenic challenge.

GCs induce important plastic changes in the brain and many of their effects, including those related to their priming and pro-inflammatory properties may play critical roles in the “yin and yang” effects of the innate immune reaction in the brain.