Anne Faulkner Lecture: The neuroimmune basis of fatigue
Prof Robert Dantzer, University of Texas Anderson Cancer Centre
In his presentation, Professor Robert Dantzer explained how sickness behaviour, which includes fatigue, is part of the normal, ‘healthy’, response to infection and usually subsides after the infection. It is triggered by cytokines released by immune cells when they detect a pathogen. Chronic fatigue may be linked to long-term activation of sickness behaviour. Professor Dantzer finishes by describing the ‘orexin’ system in the brain, which may play a critical role in fatigue and could be a target for drug therapies.
“Remember that last time we had the flu — the sleepiness, depressed mood, decreased activity, fatigue, reduced appetite, etcetera? All of this is triggered by cytokines released by white blood cells”. Professor Robert Dantzer is describing ‘sickness behaviour’, the characteristic response of all mammals to an infection. It is a biological process that exists to promote recovery and healing.
Professor Dantzer’s pioneering research helped reveal the biology of sickness behaviour He now works on cancer-related fatigue, which he believes could be a result of sickness behaviour gone wrong — and which might be related to chronic fatigue syndrome, both in symptoms and underlying mechanisms.
In his model, cancer-related fatigue is driven by white blood cells releasing tiny molecules called cytokines that act on the brain. This process is modified by risk factors, including the version of immune genes you have, neuroendocrine factors and psychosocial factors.
“Previous work on communication pathways between the immune system and the brain needs to guide us”, said Professor Dantzer, as he reviewed the long-running saga of how researchers discovered the relationship between sickness, fatigue and inflammation.
The brain’s “immunostat”
Researchers began to realise that, just like any other organ, the immune system is regulated by the brain. There must be what Professor Dantzer calls an ‘immunostat’ in the brain, and much like a thermostat in a central heating system, senses and regulates the temperature, the immunostat senses the state of the immune system and regulates it accordingly. But this requires communication between the immune system and the brain.
Work in the 1980s found evidence of two-way communication between the brain and the immune system. When they detect infection, immune cells produce molecules called cytokines (Interleukin 1, IL-1, is a key cytokine here). These molecules signal to the brain, alerting it to inflammation in the body. Back then, it was a radical idea that the immune system could produce molecules that affect the brain and physiology. It took a bit longer to discover that these same molecules also lead to changes in behaviour.
More research showed that the communication is a two-way street: the brain controls the release of molecules that regulate the immune cells, including glucocorticoids via the Hypothalamus-Pituitary-Adrenal (HPA) axis. (Glucocorticoids are widely used in medicine to damp down inflammation.)
These and other discoveries on the immune mechanisms of fever were brought together in 1988 by Benjamin Hart with his proposal that sickness behaviour is a normal and important process, part of the animals’ deliberate response to infection driven by biology. A key part of the model is that it is a temporary situation to deal with infection: inflammation –> sickness behaviour –> removal of pathogen –> restoration of normal behaviour.
Slide reproduced from Professor Dantzer’s presentation, modified slightly for simplicity
The key steps leading to sickness behaviour are:
1. White blood cells recognise invading pathogens. (At this point, the cells use receptors that identify generic ‘foreign’ markers, such as bacterial cells walls, rather than recognising specific bugs such as the flu virus.)
2. The white blood cells release cytokines in the body.
3. Immune-to-brain communication takes signal to the brain (either via the blood, or the nerves innervating the site of the body in which the inflammatory response takes place.
4. This activates microglia - the brain’s innate immune cells - which release more cytokines into the brain. So activation of immune cells in the body leads to activation of immune cells in the brain.
5. This leads to more biological changes and, ultimately, to sickness behaviour, including fatigue.
The first evidence that microglia played a critical role came in 1992, when a study showed that microglia produced IL-1 in the brain in response to inflammation in the rest of the body. Subsequent work using fMRI brain imaging shows that inflammation leads to microglia being activated throughout the brain within a few hours.
LPS – used in experiments to trigger inflammation
Many experiments that probe the role of inflammation in sickness behaviour use a molecule called ‘LPS’ to trigger inflammation. LPS, or lipopolyscaccharide, is a component of the cell wall of many types of bacteria and acts as an alarm signal to the body. Many immune cells have receptors that bind LPS, and this binding acts as a trigger that launches the immune response, including the release of cytokines. It’s a convenient way for researchers to generate a ‘clean’ signal of inflammation, and zero in on the body’s immune response, without the complications of an ongoing infection.
Sickness behaviour is flexible
Professor Dantzer made the point that while sickness behaviour is normally a standard set of responses driven by infection, it is affected by the environment too. This is the “motivational state” view of sickness behaviour. Normally, when we are sick the world no longer matters to us, what matters is taking care of the injured body – that’s exactly what the brain wants us to do – but in extreme situations this can be overridden, as the following experiment showed.
Female mice with young pups, if injected with LPS at room temperature, show lethargy typical of sickness behaviour, and won’t respond if the pups’ nest is removed. However, if pups are dispersed in the cage, the female mice will overcome their sickness and bring back their pups to the stack of cotton wool they normally use to build the nest. But if the experiment is repeated with the temperature reduced to a chilly 6 degrees centigrade, then the mother mouse will react to the harsher circumstances threatening her pups and not only bring back her dispersed pups to the stack of cotton wool but make use of the material to rebuild the nest. So behaviour depends not just on inflammation, but the environment too. Or, as Professor Dantzer said “Inflammation-induced sickness is a motivational state that reorganizes the priorities of the sick individual”. And those priorities are flexible according to the environment.
Professor Dantzer said that up to this point he’d described normal, ‘healthy’ sickness behaviour. It’s normal to feel sick in response to an infection in the same way it’s normal to feel afraid in response to a threat.
Essentially:
- The brain has an ‘immunostat’ that recognises the immune response in the body – this is the origin of sickness behaviour.
- This reorganises sick animal’s priorities.
- Crucially, sickness behaviour is normally fully reversible.
"To be healthy is to be able to become ill and recover from it…"
(Georges Canguilhem: "être en bonne santé, c’est pouvoir tomber malade et s’en relever")
Professor Dantzer moved on to what might go wrong when we don’t recover normally, asking, “Is chronic fatigue or depression a form of sickness disorder?”
Inflammation: unpicking its roles in fatigue, sickness and depression
Historically, much sickness behaviour research has focused on inflammation causing depression rather than fatigue.
However, what doctors call ‘depression’ has different elements, and fatigue counts as a big part of it:
- Mood symptoms including feelings of sadness, irritability and crying
- Affective/cognitive symptoms including self-dislike, guilt and worthlessness
-
Neurovegetative symptoms, which include the CFS/ME symptoms of fatigue, problems with sleep and concentration.
Professor Dantzer showed a fascinating slide based on the work carried out by his former student, Lucile Capuron. This slide broke down how different types of symptoms appeared at different times in cancer patients given the cytokine interferon-alpha as therapy. The fastest response comes from flu-like symptoms (malaise) that appear rapidly with each repeated dose (but fade fast due to anti-fever drugs).
But within a few days the neurovegetative symptoms start, including of fatigue, sleep problems and difficulty concentrating. After a week or so both mood and cognitive symptoms cut in.
So a problem is that when researchers said they found ‘depression’ in response to inflammation, sometimes they only meant fatigue and other CFS/ME-like symptoms. A study on an inflammation-linked disorder called Metabolic Syndrome found that there was a link of inflammation with depression overall, but that while there was a significant link for the neurovegetative symptoms, the link with mood and affective symptoms was not statistically significant.
Deconstructing fatigue – what exactly does inflammation affect?
Professor Dantzer argues if we really want to understand the biology we need to go further and ‘deconstruct’ even fatigue. The idea is to break it into the ‘neurobehavioural units’ corresponding to the way the brains works. Fatigue, said Professor Dantzer, could be seen as having two elements:
- The physical ability to do things
- Motivation: willingness or wanting desire to do things.
He said that patients they see at his cancer centre have more problems with motivation, but he also believes biological systems underpin both elements of fatigue.
Professor Dantzer gave the example of motivated behaviour and how it is affected in different ways by different aspects of inflammation. Motivated behaviour can be broken into two steps. In the case of feeding, there is
- a ‘seeking’ phase of accessing the food, then
- a ‘taking’ (or consummatory phase of eating it.
So in predators, like cats, this would be hunting and eating. It turns out that different parts of the brain are involved in theses seeking vs taking steps.
An experiment helped show the difference and how inflammation can affect both steps but at different times. If rats pressed a lever five times (seeking behaviour) they were rewarded with tasty food (the rat equivalent of “very nice wine from Bordeaux” said Professor Dantzer, who is French). The rats had free access to normal rather bland laboratory food (“like wine from Bristol”, suggested Professor Dantzer, who was speaking in a lecture hall in Bristol).
Healthy rats press the lever to get the “Rat Bordeaux”. When rats were injected with a cytokine to cause inflammation and tested ninety minutes later during the peak of sickness, they ate less ‘Rat Bordeaux’ (the food that required more energy-requiring seeking behaviour of lever-pressing), but still ate easy-access boring food (simple taking behaviour). This fits with physical exhaustion.
However, the results were different when they did a similar study on mice at a later stage (one day on) where depression would have cut in for mice. This study used grain (unexciting food) or chocolate (which mice apparently love). A single lever press was needed for grain, but ten presses were needed for chocolate. This time the LPS-injected mice injected worked less than healthy mice overall, but more of what they ate was chocolate, even though it was more work. It was if the problem was motivation – they were less likely to respond overall but if they opted for engaging in an effort, then this effort needed to be for a big incentive rather than a small one.
Similar studies have been done in humans, though they used money instead of chocolate as the incentive. Professor Dantzer said the beauty of this approach was they could study motivation both in animals and humans (and run experiments in animals that wouldn’t be possible in humans).
Orexin – the key to inflammation-related fatigue
Professor Dantzer finished his presentation by describing a recently-discovered system in the hypothalamus of the brain that plays a key role in regulating energy levels - and could be a target for drugs to treat fatigue. The orexin system senses metabolic status and the balance between feeding and energy expenditure. It responds to glucose as well as leptin, a key molecule signalling energy levels that has been implicated in CFS/ME).
The orexin system also plays a role in sleep versus wakefulness. Unlike healthy rats, those given LPS fail to become more active at night. What’s really interesting is that the reduction in activity correlates with reduced levels of orexin. However, rats given orexin as well as LPS don’t show any reduction in activity, suggesting that orexin plays a key role in activity levels.
Orexin as a treatment for fatigue?
Researchers suspected that orexin may play a similar role in the cancer-related fatigue resulting from chemotherapy. They found that giving mice chemotherapy did indeed lead to lower levels of activity, indicating fatigue and a reduction in their orexin levels. Crucially, giving mice orexin alongside the chemo restored their activity levels, again suggesting reduced orexin played a central role in fatigue. He said that there are now drugs for narcolepsy targeting the orexin system, and perhaps they could one day be used for fatigue too.
Professor Dantzer said his group are working on a test of orexin as a treatment for cancer-related fatigue.
Conclusion
Professor Dantzer summed up by saying how hard it was to study a disorder characterised by symptoms, and urged a more detailed approach, probing what is really happening in the brain:
“It’s time now to deconstruct fatigue. We cannot continue to label patients; we have to find out how their brain is working, what is behind chronic fatigue. We are doing that now in cancer patients. There is no reason not to do it in CFS/ME.”
Finally he pointed out the challenge ahead: “We know what causes fatigue, we still do not know what is responsible for the chronification of fatigue”.
This article covers most of the points in the presentation, but does not aim to be a comprehensive summary.
[article by Simon McGrath, thanks to Professor Dantzer for his amendments and approval]
The Anne Faulkner lecture was given in honour of the founder of the CFS Research foundation, who
recently died after raising more than £1 million for ME/CFS research.
Part 2 of the report will follow soon….
