Releasing the handbrake at the intersection between stress and the immune system

If you are like me, you may have noticed that you get sick following any prolonged life stress. Be it exam season, the holidays, or awaiting an upcoming social event, it seems that as soon as the stressor is over, you come down with the flu. In university, I would come home from the semester with a fever every time. 

Doctors and Scientists call this 'the let down' effect and have observed it in numerous contexts, including flare-ups of chronic conditions following the holidays. Scientists believe that this effect is the result of stress-induced suppression of the immune system. As your stress wanes, so too does its grip on the immune system. 

When faced with a stressor, your body releases glucocorticoids (namely cortisol), a specialized family of hormones that are meant to prepare your body for the upcoming stress. These have various effects, including altering your metabolism, memory, emotional state, and -the topic of today's section – the immune system. The relationship between glucocorticoids and the immune system is complex. However, crucially, in many cases, the glucocorticoids' down-regulate' the inflammatory response of the body's immune system. This glucocorticoid-based regulation of the immune system is critical for the body to regulate its immune response. 

In fact, scientists and doctors have been exploiting this relationship for decades. You may know somebody (or you yourself) may have taken a corticosteroid to treat a condition. These corticosteroids (of which glucocorticoids are a sub-family) hormone medications mimic the body's natural stress-hormone based immune suppression system; they are often used to treat conditions where the immune system is overactive or otherwise maladaptive. 

Critically, the region of the brain that controls the stress response is sensitive to a systemic immune response in the body. In essence, when the brain senses immune activation, it triggers the release of stress hormones to suppress the immune activation. This is a crucial point of negative feedback for the body's immune system. However, it is not fully understood how the brain senses and triggers the stress response to inflammation. Emerging research from the Inoue Lab at The University of Western Ontario elucidated at least one pathway by which this critical feedback occurs. 

The region of note is called the hypothalamus – a small walnut-shaped region located near the base of the brain. The hypothalamus oversees several bodily functions, including regulating your temperature and metabolism. It can be helpful to think of the hypothalamus as the thermostat of the body – that is - when the thermostat senses the temperature is either too high or too low, the thermostat will kick on the heat or air conditioning to regulate the temperature to the target range. In comparison, when a body state (temperature, hunger, movement) is outside of the acceptable range, the hypothalamus transmits the necessary signal to restore the body to the desired range; this is a phenomenon called homeostasis. 

A small subset of the hypothalamus called the Paraventricular nucleus (PVN) drives the stress response. Here, neurons (brain cells) release a specialized chemical called corticotrophin-releasing hormone (CRH) to trigger a pathway that eventually results in the release of the aforementioned glucocorticoids. These neurons – aptly named CRH-releasing parvocellular neurons – receive a wide variety of input from many brain regions. This is crucial for these neurons to respond to the large array of stress types a modern human may encounter. Critically, these neurons are receiving near-constant excitatory and inhibitory signaling. On the one hand, the excitatory signaling tells the neurons to release CRH. In contrast, inhibitory signaling tells the neurons not to release any CRH. The neuron then weighs the incoming excitatory and inhibitory signaling in order to 'decide' what to do. In fact, scientists believe that a delicate balance between excitatory and inhibitory signaling is critical for hypothalamic functioning. Think of it like having a devil on one shoulder and an angel on the other, both balancing each other out. 

In concert with their previous work, the Inoue lab investigated the role of the pro-inflammatory immune signaling chemical Prostaglandin E2 (PGE2) in driving the stress response. When the body is faced with an immune challenge, it is thought that PGE2 is released into the brain, which makes it a logical target for investigation. To begin with, the researchers recorded the inhibitory signaling at baseline. To do so, they employed a technique called 'patch-clamp' which allows them to record from a single neuron in the brain. Using this, they could 'listen-in' on the inhibitory input that a single parvocellular neuron receives. As expected, there was a near-constant inhibitory signal streaming into the single neuron. 

Next, the researchers flooded the hypothalamus with PGE2. Surprisingly, PGE2 caused a decline in the frequency of small incoming inhibitory inputs called inhibitory postsynaptic currents (IPSC). In essence, the researchers observed a decline in inhibitory signaling. To further assess the role of PGE2, the researcher's stimulated nearby cells to generate large inhibitory inputs called inhibitory postsynaptic potentials (IPSP). At this point, they watched as potent inhibitory signaling from the stimulated cells decreased in amplitude following the application of PGE2. Finally, the researchers used statistical analysis to determine that the suppression of PGE2 signaling was occurring at the source, rather than the result of an internal mechanism of the CRH-releasing neurons.

In sum, PGE2 weakened the strength of the incoming inhibitory signaling to the CRH-releasing neurons. But what are the physiological consequences of this? The researchers theorize that as the body responds to an immune challenge, PGE2 is released in the hypothalamus. Next, the PGE2-induced decline in inhibitory signaling, in turn, allowed excitatory signaling to overwhelm the parvocellular neurons, subsequently leading to the release in CRH. This eventually cascades into the release of glucocorticoids, which – as a loop suppress the body's immune response. Think of the parvocellular neurons like a car with the accelerator floored (representing the excitatory signaling) and the handbrake engaged (representing the inhibitory signaling). As soon as the handbrake is disengaged (or the inhibitory signaling is removed), the car tears off at full speed - or in this case - the neurons release CRH.

Moreover, coming back to our thermostat analogy, this study represents a prime example of such 'thermostat' behaviour. The hypothalamus senses something is amiss with the body (immune activation via PGE2). It takes the necessary steps (activation of the stress response) to bring the body back into balance.

The Inoue Labs' findings represent a vital step in the understanding of the stress-immune relationship. This may become critical in recognizing what happens when this relationship breaks down,  such as in Cushing's syndrome. Further research in this area has uncovered the role that non-immune stressors may play in the immune-induced stress response and vice versa.