To view this post in German click here/ Für die deutsche Version hier klicken:
The brain is the central “control system” for the functions of our body. Our muscles, for example, move because nerve fibres attached to the muscles transport information from the brain to initiate muscle contraction, resulting in movement. The question posed in our publication of the month is, can the brain also control the local process of inflammation?
During inflammation, for example following a cut of the skin and an infection with bacteria, the first immune cells to respond are from the innate immune system. This first wave can directly fight pathogens but also activates a second line of defence – the adaptive immune system. This process occurs locally in the affected tissue.
Kim et al. show that following an infection outside of the brain and subsequent rise in innate immune mediators, the brain can quickly mobilise adaptive immune cells in the spleen and fat to help fight the infection.
The brain is a so called immune-privileged organ. The blood-brain-barrier protects the brain from infiltrating immune cells and mediators in order to prevent immune cell mediated inflammation in the brain.
How can the brain sense local inflammation?
To model local infections, the researchers injected mice with Listeria monocytogenes, a bacteria known to cause an innate and adaptive immune response. During the first three days of the infection the levels of TNFα, a mediator of innate immune function, rises in the blood. In addition, the numbers of adaptive immune cells called T and B cells increase both in the fat and spleen of infected mice. Interestingly, TNFα levels are also up in cerebrospinal fluid (CSF). CSF is produced by the brain and baths both the brain and spine. An increase of inflammation markers in the CSF can therefore inform the brain of peripheral (outside of the brain) occurring infections.
The authors do not speculate how TNFα enters the CSF, which should be isolated from the blood TNFα by the blood-brain-barrier. However it is known that cytokines can enter the brain via certain routes and Kim et al. state that the hypothalamus is known to have a weaker blood-brain-barrier. As the hypothalamus also expresses high levels of the TNFα receptor (TNFR) experiments concentrating on this part of the brain were needed.
In order to see if the increased levels of TNFα in the brain, rather than other effects of the infection, influence the rise of adaptive immune cells during the Listeria infection, the researchers injected TNFα (at similar doses as measured during infection) into the hypothalamus of mice. Indeed T and B cell numbers were increased in the fat and spleen of TNFα injected mice, similar to what is seen in Listeria infected mice. The frequency of innate immune cells such as macrophages was unchanged.
Using both chemical and genetical blockage of TNFα signalling the hypothalamus via site-specific injection of TNFα antagonists or the use of TNFR deficient mice, Kim et al. showed decreased accumulation of adaptive immune cells during Listeria infection. Additionally, TNFR deficient mice were more vulnerable to bacterial infections, probably due to their impaired adaptive immune response.
In contrast to the loss-of-functions experiments described above, where a gene or molecule is blocked to analyse the effect, gain-of-function experiments are used to see what effect the introduction of a gene or molecule has on a studied system. In this study, reintroduction of TNFRs into the hypothalamus of TNFR-deficient mice using a viral expression system showed increased numbers of adaptive immune cells after infection proving the importance of TNF signalling in the hypothalamus in order to mobilise immune cells.
How can the brain signal to the immune system?
While it’s easy to see how the brain can modulate tissues such as muscles, it is less clear how the brain reaches immune cells which can move around the body. The brain does not only act via never fibres, it also produces neurotransmitters and hormones to control the body. Immune cells are known to express receptors for these soluble mediators produced by the brain – which is one way the brain can modulate immune cells.
Given the increase in T and B cells in the fat, Kim et al. had a deeper look into the fat of TNFα injected mice. They found increased signs for the breakdown of fat (called lipolysis) and high levels of free long-chain fatty acids and leptin in the blood stream. So it seems that innate immune mediators can lead the brain to mobilise the adaptive immune system via the breakdown of fat. Injection of several fatty acids into the blood of healthy mice supported this idea by inducing an increase in T and B cells in the fat and spleen, similar to what is seen in Listeria infected or TNFα injected mice.
It is known that the fat content can influence the immune system. Low amounts of fat can lead to decreased immune responses while obesity has been linked to increased inflammation.
So what happens to the brain-fat-immune axis if the fat is abnormal?
Analysing the effect the amount of fat-storage has on the brain-immune regulation, the authors found that due to low-grade inflammation in the hypothalamus of obese mice, the animals were non-responsive to TNFα injections into the brain and showed no increase in adaptive immune cells post injection. This suggests that while the brain can influence the adaptive immune system during acute infection, the level of fat-storage plays an important role in this process. These findings implicate a role for fat as endocrine (=hormone releasing) organ, which can influence the immune system and other organs by releasing leptin and fatty acids.
It remains to be seen what role the brain-fat-immune axis plays during chronic inflammation disorders such as obesity or autoimmune diseases. Given the data in obese mice the pathway seems less or not functional anymore. Are there compensatory mechanisms? Given my neuroscience background I also wonder what this research could mean for neurodegenerative disorders where in the case of Alzheimer’s disease a leaky blood-brain-barrier has been reported alongside changes in the immune system of the patients. Could it be that the brain-fat-immune axis is more active in these people leading to more inflammation?