English summary

In document University of Groningen Neuroinflammation in depression Dobos, Niki (Page 116-120)

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Growing body of evidence supports the notion that disturbances in both, the peripheral and central immune system contribute to the development of major depression (MD).

Chronic inflammatory diseases, e.g. Crohn’s disease, rheumatoid arthritis, chronic obstructive pulmonary disease or immune therapies, like interferon alpha or interleukin-2 treatment in cancer patients are all associated with frequent occurrance of MD. Moreover, neurodegenerative diseases, such as Alzheimer’s disease, Multiple sclerosis, which are also considered as inflammatory diseases have been revealed to be accompanied with depression.

In the last few decades, depression research became one of the hottest research topics mainly due to the fact, that major depression is the leading cause of disability, more than 350 million people are affected worldwide. Moreover, lost productivity and rising costs of healthcare of MD patients leads to vast financial damage. Although there are known effective therapies for MD, remarkable proportion of the patients is resistant to any kind of antidepressant therapies, thus, the better understanding of the neurobiology of MD is crucial in the development of novel therapeutic strategies. Therefore, the rationale of the present thesis was to investigate the obvious role of neuroinflammation in depression.

In particular, our research has been based on the macrophage hypothesis, which emphasizes the role of the cytokine signaling in the development of depression.

As mentioned above, multiple inflammatory processes play a detrimental role in the development of depression as well as in neurodegenerative diseases. However, previously the brain was irrefutably believed to be an immune privilege organ, this concept has been disproved by many studies. Continuous migration of immune cells through the blood brain barrier contributes to the homeostasis of the periphery and the brain. Cerebral inflammation is associated with the activation of microglia, the resident immune cells of the central nervous system (CNS). Upon immune activation, microglia become activated and start producing and releasing pro-inflammatory cytokines, such as tumor necrosis factor ơ (TNFơ) or interferon ƣ (IFNƣ), subsequently initiating an inflammatory cascade. Under experimental conditions, in vitro or ex vivo, monitoring neuroinflammation is widely used.

Although in vivo visualization of neuroinflammation has developed rapidly in the last years, the refinement, optimalization and synchronization of structural and functional techniques must be further investigated. Visualization of microglia activation is one of the most conventional procedures in the detection of neuroinflammation. In the present thesis, Chapter 2 reviews basic neuroinflammatory mechanisms and particularly, the role of TNFơ in neuroprotection and neurodegenerative diseases. Furthermore, general neuroimaging techniques are also described.

Recently, immunmodulatory cytokine-therapies or targeting the specific cytokine-receptors have gained mounting interest in research. For instance, the biological effects of TNFơ and its two main receptors, tumor necrosis factor alpha receptor 1 (TNFR1) and tumor necrosis factor alpha receptor 2 (TNFR2) have been extensively investigated in neuropsychiatric disorders. However, some promising results bring us closer to the therapeutic use of receptor agonists or antagonists, due to the complexity of the receptor crosstalk and the important physiological functions of TNFơ, further examinations are necessary.

Additionally, aging has also been shown to influence the cytokine signaling and receptor function. Therefore, in Chapter 3 we intended to study the physiological role of TNFR1 and TNFR2 on cognition, behavioral and neuromuscular functioning in young and aged mice

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using wildtype, TNFR1 and TNFR2 knock out mice. The most important finding of this chapter was, that TNFR2 has a fundamental role in hippocampus dependent learning and memory and muscle functioning.

It has been shown that neuroinflammation and pro-inflammatory cytokines are able to activate an enzyme, indoleamine 2,3-dioxygenase (IDO) that catalyzes the first and rate-limiting step of tryptophan catabolism, along the kynurenine pathway. According to the well-known monoamine hypothesis of depression, the disturbance of the serotonin system is responsible for the depressive symptoms. Nevertheless, this hypothesis is not able to exclusively characterize the neurobiology of depression, rather should be combined with others, like the cytokine-hypothesis and focus on a more complex concept. In this approach, since serotonin is synthetised from tryptophan, and IDO is activated upon immune challenges, the question is given, whether and how IDO is involved in the pathophysiology of depression.

In Chapter 4 we investigated in our experimental animal model, how cerebral inflammation is involved in the expression and activation of IDO and whether the activation of IDO is responsible for the depressive-like behavior. Neuroinflammation was monitored by small animal positron emission tomography using an activated microglia marker and the behavior of the mice was observed. We could demonstrate that inflammation induced depressive-like behavior is dependent on the activation of IDO, as it was proven in a group of mice treated with a competitive IDO-inhibitor. Interestingly, IDO was found to be upregulated in the brain stem of the animals, the most important serotonin producing area of the brain.

As indicated before, interferon therapies are often accompanied by depressive-symptoms.

Therefore, the mechanisms behind the effects of interferons are in major focus of research.

Interferons are immune modulators and potent activators of IDO, thus, consequently might be responsible for depression. Indeed, research studies have reported positive correlation between the activity of IDO, amount of tryptophan catabolites, and the severity of the depressive symptoms. Fortunately, Prof. Dr. Marco Prinz and Dr. Thomas Blank kindly offered to test a newly developed interferon ơ/Ƣ receptor knock out mouse line and our collaboration aimed to unravel the action of interferon Ƣ (IFNƢ) in concern with neuropsychiatric dysfunctions. In Chapter 5 we established, that 7 consecutive days of IFNƢ injection is sufficient to provoke the depressive-like behavior and cognitive impairment in mice. Moreover, the use of the IFNơ/Ƣ receptor knock out strain we were able to show that IFNƢ acts directly through the IFNơ/Ƣ receptors resulting in the abovementioned behavioral changes. Furthermore, in accordance with previous studies and the findings of Chapter 4, we found elevated IDO expression in the brain stem in wildtype animals treated with IFNƢ, allowing us to hypothesize that IFNƢ induced IDO activation is responsible for the development of depressive-like behavior and cognitive impairment.

Overall, the novel findings of this thesis further support the cytokine-hypothesis and provide evidence for the involvement of the kynurenine pathway and the upregulation of IDO in major depression. As further hypothesized and discussed in Chapter 6, the characterization of the signaling mechanisms underlying the regulation and activation of the kynurenine pathway could open a new avenue in the development of novel antidepressant therapies.

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CHAPTER 8

In document University of Groningen Neuroinflammation in depression Dobos, Niki (Page 116-120)