How being sick could make you sicker: The role of peripheral inflammation in depressive disorders.

Valentina Bart | 01 April 2021

“Mens sana in corpore sano” – a healthy mind in a healthy body

Mental health is a topic that is becoming increasingly important in everyday life. Presently, 1 in 6 children between the ages of 5 and 16 struggle with mental health issues, with the NHS reporting mental health problems to be the biggest cause of disability in the UK. It is often said that physical exercise is important for mental well-being. Taking this idea further and looking at current research, it becomes clear that a sick body could severely harm your mental health. 

But how does physical sickness link to our mental wellbeing? 

Inflammation is the natural reaction of the organism to an insult, such as exposure pathogens, severe trauma, stress, obesity, and normal aging. In an initial response, fast-responding immune cells, which are your body’s first line of protective soldiers, recognise pathogens by their specific proteins. Your “soldier cells” respond to these proteins by producing inflammatory mediators, which is the equivalent of sending out an emergency response team to do some damage control. This reaction causes the typical symptoms of inflammation: redness, swelling, pain, heat, and possibly loss of function. In an otherwise healthy organism this immune response is balanced so that after the damage caused by inflammation anti-inflammatory processes are induced to tidy up the mess. Eventually, that would restore homeostasis and  bring you back to your normal healthy self.

While these processes occur in most areas of the body, the brain was long considered an immune privileged site, meaning it was thought not to be affected by any of these immune processes occurring in the blood. However, over the last decades the idea that the central nervous system (CNS) is protected from inflammation has been challenged from two directions. On the one hand, there are CNS diseases such as Alzheimer’s disease and multiple sclerosis which are characterised and directly driven by immune responses and inflammation in the brain. On the other hand, it has been noted that peripheral immune responses, happening elsewhere in the body, also influence brain health. One example is “sickness behaviour”, a state of depressed mood, fatigue, and disrupted appetite associated with diseases. It drives sick individuals to rest and thus allows energy to be redirected to the immune system to combat pathogens. This is why you may feel lethargic and yucky when you get the flu. Interestingly, there is an overlap between the symptoms of “sickness behaviour” and major depressive disorder (MDD) which has led researchers to investigate the role of the immune system in neuropsychiatric disorders. 

MDD is a severe form of depression with symptoms that include loss of appetite, sleep disruption, fatigue and feelings of worthlessness. With a great increase in suicide (Chesney, Goodwin & Fazel, 2014) and around 30% of patients not responding to the standard treatments (Rush et al., 2006). It is troubling how little we know about this disease. Although there is a genetic component, this seems to interact with environmental factors, such as stress and trauma, to develop full blown MDD (Caspi et al., 2006). 

Additionally, several studies have described a direct link between inflammation and MDD. For example, the incidence of MDD is increased in patients suffering from inflammatory diseases such as rheumatoid arthritis (Dickens et al., 2002) or cancer (Linden et al., 2012) and vice versa. Also, approximately one-third of people struggling with MDD show increased inflammatory biomarkers in the absence of medical disease (Liu, Ho and Mak, 2012). Lastly, variants in some genes associated with inflammation are also associated with increased risk of MDD (Gałecki et al., 2012). With this increasing body of evidence, it is becoming very clear that peripheral inflammation is very important when it comes to understanding the biological mechanisms driving depression.

To appreciate how peripheral inflammation can affect the brain, we will follow two such pro-inflammatory mediators on their journey; IL-1 and TNF.

Naturally, we start at the beginning – the moment when our soldier immune cells are activated by the intrusion of pathogens. As a first line of defence, they produce and release a variety of pro-inflammatory substances, the job of which is to attract more specialised immune cells and direct the immune response. This is crucial, since different types of these specialised  cells are trained to respond to different types of pathogens more efficiently than the brute force offered by the soldier cells. You wouldn’t want an air force unit to deal with a marine attack. This is where IL-1 and TNF come in. 

During a regulated immune response, these cytokines alert your specialised forces, before being removed by anti-inflammatory signals to resolve inflammation and restore homeostasis. Although these inflammatory processes are great at dealing with pathogens, they also inflict a lot of self-damage which can easily be repaired after the inflammation has died down… assuming it does die down. If it doesn’t, this is known as chronic inflammation and can cause a lot of issues since the body is unable to repair itself. Indeed, studies consistently report high levels of pro-inflammatory mediators in patients struggling with depression (Dahl et al., 2014) and inflammation can even predict symptoms of depression later in life (Khandaker et al., 2014).

So, as now we know their role in an immune response, how could IL-1 and TNF affect mental health?

Crucially, they need to affect brain-resident cells. If they are present in the body in very high quantities, they can directly cross into the CNS. Considering the brain is the master regulator of the whole body and mediators are typically kept in a delicate balance, this can be dangerous. This is illustrated by the fact that while low doses of IL-1 are needed for memory formation, high levels as observed during inflammation actually impair the same process (Kelly et al., 2003), which is reflected in memory disturbances experienced by individuals with MDD (Lam et al., 2014).

Within the brain, IL-1 also activates the hypothalamic-pituitary-adrenal (HPA) axis, a complex system of glands in the brain and in the abdomen that influence each other and regulate how the body responds to stress. This axis is thought to be overactivated in MDD, causing an overproduction of stress-related hormones. Stress hormones once again have been linked to impaired memory formation in animal models (Alfarez, Joëls and Krugers, 2003).

Stress hormones also affect the release of neurotransmitters (brain hormones) and how they act on their receptors. One example is the serotonin 1A receptor, the expression of which in the brain is decreased by stress hormones (Meijer et al., 2001). This receptor normally binds to serotonin, the “happy chemical” that is known to play a role in depression.

When two neurons interact with each other in what is called a synapse, the one sending out a signal is called presynaptic, and the receiving neuron is called postsynaptic. Both of these neurons can express the Serotonin 1A receptor, but it will play different roles. When the receptor is expressed on the firing (presynaptic) neuron, it takes up serotonin released by the very same neuron and thereby prevents it reaching the receiving neuron. This is bad, as serotonin is important in regulating your mood via serotonin actually reaching the postsynaptic neuron. This presynaptic receptor is acted on by selective serotonin reuptake inhibitors (SSRIs, drugs prescribed for MDD) which cause its desensitisation, making serotonin available to the receiving neuron and alleviate symptoms of depression.

In contrast, the same receptor on the receiving neuron does not seem to be affected by SSRIs, which is good, as this receptor needs to bind serotonin to transmit the “happy signal”. This receptor however is affected by stress hormones, and a decrease of the postsynaptic receptor numbers has been linked to suicide by depression (Cheetham et al., 1990). 

IL-1 and TNF can also affect the brain without even gaining access. That is because they can interact with cells lining the barrier to the brain and cause them to produce other mediators that then act on brain-resident cells. In experiments with mice, researchers found that the injection of TNF triggers these brain-bordering cells to produce a lipid that has also been detected in the fluid surrounding the brain of depressed patients (Linnoila et al., 1983). Within the CNS this lipid stimulates the production of other pro-inflammatory cytokines that will further disturb the balance and has also been implicated in the activation of the HPA axis that we discussed before (García-Bueno, Serrats and Sawchenko, 2009).

In one last trick, IL-1 and TNF do not even have to be in close proximity to the brain to affect mental health: they can stimulate the vagus nerve which runs between the brain and the abdomen and relays information from the periphery into the brain. This is the major component of the parasympathetic nervous system involved in the control of heart rate, digestion, mood, and immune responses. In rats, researchers showed that peripheral IL-1 activates the afferent vagus nerve (Hansen et al., 2001), thereby informing the brain of inflammation detected in the body. By disrupting signalling through this nerve, the researchers demonstrated that they could prevent sickness behaviour in rats without affecting the amount of circulating IL-1 (Bluthé et al., 1994).

So, since IL-1 and TNF are thought to be key players involved in the symptoms of MDD, could they be a potential therapeutic target for MDD? Indeed, various anti-inflammatory agents have demonstrated anti-depressive effects: data from clinical trials in which people received medications that block inflammatory cytokines to treat medical diseases showed significant improvement of depressive symptoms (Kappelmann et al., 2018). Similar results were reported from another study where 5 out of 6 anti-inflammatory drugs could improve depression symptoms compared to placebos (Köhler‐Forsberg et al., 2019). While these are important findings, studies have failed to show consistent associations between inflammatory cytokines and disease severity, suggesting that only certain subtypes of depression are based on or exacerbated by inflammatory processes. Indeed, only a fraction of patients struggling with mental diseases present with markers of peripheral inflammation such as IL-1 and TNF. 

A study comparing cancer patients receiving pro-inflammatory cytokine therapy with MDD patients with no physical illness showed an overlap in depressive symptoms. However, this study also showed that psychomotor retardation and weight loss were stronger in depressed cancer patients while increased feelings of guilt were stronger in (otherwise healthy) MDD patients (Capuron et al., 2009). While this study investigated a very small number of people, the results fit with the idea of a high heterogeneity of mood disorders that would respond to different types of treatments. It is unclear at the moment whether the group of patients that benefits from anti-inflammatory drugs overlaps with the group of people that does not respond to traditional MDD medication.

To date, most studies of the interaction between immune activation and psychiatric diseases provide correlational evidence rather than causal relationships. While animal studies can show the direct production of depressive symptoms following cytokine exposure, such results cannot directly be translated into the complex reality of human mood disorders. Nevertheless, the link between peripheral inflammation and mental health can help explain mental side effects of immune activating therapeutics for the treatment of cancer. The mental health of patients receiving such medication should carefully be monitored.

In the future, continuous research into how exactly inflammatory mediators could trigger or exacerbate mental conditions will not only help us understand mental disease heterogeneity, but potentially also result in the development of immune-based strategies that might help improve the lives of mental health patients that do not respond to current therapeutics.

Editors: Steliana Yanakieva and Katie Sedgewick

References:

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