The Kynurenine Pathway: Implications for inflammation and mood

When you’re sick, the last thing you want to do is drag yourself to work and deal with your normal routine. Even socializing with friends does not sound pleasant anymore. You may experience low energy, sleep issues, low appetite, and low mood, to name a few. This “sickness behavior” shares many of the same symptoms as depression. This behavior is thought to have evolved to encourage people to slow down and rest when ill in order to maintain the resources needed to clear an infection¹. In most cases, these symptoms will be short lived, and the body will return to normal once the infection has cleared. However, in instances of long term immune up-regulation, these symptoms may become more persistent and result in a long term depressive state. Over the years, a great deal of research has linked inflammation to depression, and many different theories regarding the mechanism by which this may occur have been proposed.

Figure 1. Neuropsychiatric side effects of immunotherapies based on the administration of pro-inflammatory cytokines. Image from Schiepers 2005.

Immune cells produce cytokines which help regulate immune responses in the body. The activities, as well as the classifications, of cytokines vary greatly. Typically cytokines are discussed in the context of pro-inflammatory and anti-inflammatory capacities. Pro-inflammatory cytokines activate the inflammatory response and anti-inflammatory cytokines dampen that response. Cytokines are suspected to access the brain by crossing the blood- brain barrier in vulnerable areas, being transported by active transport, as well as being produced directly in the brain by astrocytes and microglia³.

The link between pro-inflammatory cytokines and depressive symptoms was discovered by observing patients receiving immunotherapy. Certain pro-inflammatory cytokines are sometimes given as immunotherapy for disorders such as cancer, chronic hepatitis C, and multiple sclerosis (MS). This therapy has been shown to cause a variety of side effects in patients, many of which are similar to symptoms of depression³. Figure 1 shows the different cytokines given as immunotherapy and the neuropsychiatric effects they can have on patients³.

The exact mechanism by which pro-inflammatory cytokines cause depressive symptoms in patients is unknown; however, as stated previously, many different mechanisms have been proposed. Many researchers believe that both chronic stressors and the presence of pro-inflammatory cytokines in the central nervous system influence similar pathways and result in similar consequences. Some of these consequences include: increased corticotrophin releasing hormone (CRH) leading to increased glucocorticoid levels, variations in monoamine levels and activity, and alterations in different growth and anti-apoptotic factors leading to decreased neuroplasticity². One of the most extensively studied consequences is the variation in monoamine levels and activity, specifically of serotonin.

Inflammation has been shown to affect serotonin through activation of the kynurenine pathway. Pro-inflammatory cytokines activate the enzyme indoleamine 2,3-dioxygenase (IDO). IDO shuttles tryptophan, the precursor to 5-hydroxytryptophan (5-HTP), down the kynurenine pathway rather than down the pathway that would result in the synthesis of serotonin (Figure 2). Activation of the kynurenine pathway can result in depletion of tryptophan and consequently, depletion of serotonin. Furthermore, 5-HTP and serotonin itself can be substrates for IDO leading to further depletions⁴.

Figure 2. Indoleamine 2,3-dioxygenase (IDO) degrades tryptophan through the kynurenine pathway. Image from Dantzer 2008.

In addition to decreasing serotonin levels in the body, the kynurenine pathway also results in the synthesis of multiple metabolites that can have neurotoxic effects. These metabolites include 3-hydroxy-kynurenine (3-OH-KYN) as well as quinolinic acid. 3-OH-KYN exerts its damaging effects by increasing reactive oxygen species (ROS) in the brain. This increase in ROS leads to oxidative stress and possibly neuronal apoptosis⁴. Overproduction of ROS is linked to an increase in Monoamine oxidase (MAO) activity, which could deplete monoamine levels in the brain leading to a depressed mood⁴. Quinolinic acid is a potent N-methyl-D-aspartate (NMDA) receptor agonist. Overstimulation of these receptors leads to an increased calcium influx into target neurons resulting in neuronal damage⁴. Increased influx of calcium into cells may also lead to the generation of ROS⁴. Both metabolites have been found to be elevated in certain neurodegenerative disorders such as Huntington’s disease and Parkinson’s disease⁴.

The increase in IDO activity brought about by increased pro-inflammatory cytokine levels is just one way in which the immune system affects the nervous system. There are undoubtedly many other mechanisms to be investigated in which the immune system and nervous system can affect one another. For patients who present with depressive symptoms, it may be beneficial to investigate possible underlying inflammatory issues. Full symptom relief is unlikely to be achieved until the underlying inflammatory issue is controlled or resolved.

Guest author: Alyson Betcher is a member of the Clinical Support & Education Department at NeuroScience, Inc. and one of the resident experts in psychiatric disorders.

References:

1. Anisman, A. (2009). Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. J Psychiatry Neurosci; 34(1): 4-20.

2. Hayley, S., Poulter, M., Merali, Z., Anisman, H., (2005). The pathogenesis of clinical depression: stressor and cytokine – induced alterations of neuroplasticity. Neuroscience; 135: 659-678.

3. Schiepers, O., Wichers, M., Maes, M., (2005). Cytokines and major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry; 29: 201-217.

4. Wichers, M., Maes, M. (2004). The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression. J Psychiatry Neurosci; 29(1): 11-17.

5. Dantzer, R., et al. (2008). From Inflammation to Sickness and Depression: When the Immune System Subjugates the Brain. Nature Reviews Neuroscience, 9(1): 46–56.