Does arginase mediate immune suppression in the brain?

This week I want to talk about an interesting enzyme: Arginase-I (Arg1) and its metabolic pathway in an immune microenvironment. Arg1 is a cytosolic protein that is involved in the urea cycle. Specifically, it catalyzes the hydrolysis of L-arginine to L-ornithine and urea. It has been shown that the expression of Arg1 by macrophages has an important role in tumor growth. Macrophages that are recruited into the tumor microenvironment (tumor associated macrophages) express high levels of Arg1 resulting in the depletion of arginine – an essential nutrient required for T cell metabolism. Cytotoxic T cells, therefore, can no longer function and inhibit the tumor cells from proliferating. Arg1 is implicated in several inflammatory diseases as well as in autoimmunity. Arg1 plays a significant role in mediating immune suppression and blocking its metabolism is a novel strategy in preventing tumor growth and other inflammation-related conditions.

T cell suppression by MDSC
Myeloid-Derived Suppressor Cell suppresses cytotoxic T cell function through Arg1 metabolism. (IFNγ, IL-4, and IL-13 are cytokines that induced MDSC activation)

One hypothesis is that the immune suppressive cells in other immune microenvironments in the body must be similar to the Myeloid-Derived Suppressor Cells (MDSCs) that induce T cell suppression in the cancer microenvironment. The question is, do such immunosuppressive cells express increased levels of Arg1 and act through the Arg1 metabolic pathway? Since I am interested in the brain and neurodegeneration, this hypothesis can be extended to the brain immune microenvironment. Microglial cells in the brain also upregulate Arg1 and are neuroprotective in nature (in a healthy brain). These cells are the resident macrophages of the central nervous system and function by phagocytosing cell debris and toxic misfolded proteins (that eventually form aggregates and lead to neuronal death as seen in Alzheimer’s disease) out of the brain environment. The question now is – do the microglial cells exhibit immunosuppressive behavior by altering their Arg1 metabolism?

Kan et al., 2015, recently showed that CD11c positive microglial cells are immunosuppressive in the CVN-AD mouse model and that immune suppression is caused due to the deprivation of arginine (increased levels of extracellular Arg1 causing decreased levels of total brain arginine). What isn’t explicitly mentioned in this study is that arginine is also the substrate for nitric oxide synthase (NOS) that makes nitric oxide (NO) in an alternate L-arginine metabolic pathway. L-arginine is a substrate for both Arg1 and NOS. The Arg1 pathway polarizes the macrophages to M2 phenotype and the NOS pathway polarizes the macrophages to the M1 phenotype (Rath et al., 2014). The current model of microglial activation in the CNS is limited to these two polarized states, where, the M1 microglia are neurotoxic and the M2 microglia are neuroprotective. Arg1 is upregulated in microglia in the healthy brain and aids in phagocytosis of misfolded proteins and other cell debris. The classical microglial activation is through the M2 phenotype wherein the induced nitric oxide synthase (iNOS) is upregulated thereby accelerating inflammation in the brain (neuroinflammation is one of the hallmark characteristics of several neurological diseases such as Alzheimer’s Parkinson’s, Multiple Sclerosis, Traumatic Brain Injury, etc).

M1 and M2 microglia
The current model of microglial activation is limited to the Arg1-mediated M1 and iNOS-mediated M2 polarized states.

So, if an immunosuppressive cell exists in the brain, is it possible that the immune suppression is regulated through the M2 activation and that M1 activation is absent? In other words, L-arginine is metabolized through the Arg1 pathway and not through the NOS pathway. Other questions to consider: MDSCs upregulate both Arg1 and iNOS – so how does that fit into the two-state polarization model? How does iNOS modulate MDSC activity? We know that increased NO expression by MDSCs increases T cell suppression in the tumor microenvironment. Currently, both Arg1 and iNOS inhibitors are being developed to block the immune suppressive activity of MDSCs in the cancer microenvironment. However, understanding immunosuppression in the brain is still a long way to go and the idea is not widely accepted within the neurobiology community (my understanding from the currently available literature or published studies). Investigating this mechanism in the brain will be useful in developing potential therapeutic strategies for treating neuroinflammation and neurodegeneration.

References:

  • Kan MJ, Lee JE, Wilson JG, et al. Arginine Deprivation and Immune Suppression in a Mouse Model of Alzheimer’s Disease. The Journal of Neuroscience. 2015;35(15):5969-5982. DOI:10.1523/JNEUROSCI.4668-14.2015.
  • Rath M, Müller I, et al. Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front. Immunol., 27 October 2014. DOI: https://doi.org/10.3389/fimmu.2014.00532
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Stress – it’s all in your head!

Stress is an interesting body response that is stimulated by our brain due to incoming auditory, visual and/or somatosensory signals. It is how we feel and how our body reacts when we encounter an imbalance in the normal rhythm of life. Watching a horror movie, coming face to face with a deadly creature or simply feeling overwhelmed due to daily tasks may all evoke stress. How does our brain respond to a stimulus that elicits fear and anxiety?

The key areas of the brain that are involved in stress are the thalamus, hippocampus, amygdala, and the prefrontal cortex. The thalamus located in the forebrain processes the incoming visual and auditory signals and relays them to the prefrontal cortex and the amygdala. The prefrontal cortex is the hub for executive function. With respect to stress, it gives meaning to the relayed signals and makes us conscious of what we see and hear. This part of the brain is also critical for ‘turning off’ the stress response once the condition is passed.

The Neurobiology of Stress - Brain regions involved in stress response
The Neurobiology of Stress – Brain regions involved in stress response

The amygdala is the emotional center of the brain and is responsible for triggering the stressful response. It is a part of the limbic system and is located deep within the temporal lobes of the brain. The amygdala also drives the body’s sympathetic nervous system to initiate anxiety that is associated with stress. This includes increasing the heart rate, blood pressure, hyperventilation of the lungs and increasing perspiration.

Finally, the hippocampus located in the medial temporal lobe stores the memory linked to a particular stress response and allows the brain to access these memories when the same visual and auditory triggers of stress are encountered later on.

It is also essential to mention the role of the hypothalamus and the linked pituitary gland that pumps out high levels of cortisol – “the stress hormone”. Recent studies suggest that cortisol can damage and kill brain cells, especially that in the hippocampus. (The hormonal response of stress is in fact a huge area of study with lots of factors involved.)

A critical question in this area of study that interests me is, “How much stress is bad for us? Can a little stress actually be helpful?” It turns out that acute stress (short-lived, unlike chronic stress) may actually be good for us. New research suggests that it conditions the brain for improved performance by inducing an increased level of alertness, behavioural and cognitive performance. This may explain why we get most of work done when we’re under pressure!

Completed my first MOOC – Understanding the Brain: The Neurobiology of Everyday Life

I am excited to have successfully completed my first ever massive online open course, “Understanding the Brain: The Neurobiology of Everyday Life” with distinction. Taught by Professor Peggy Mason at The University of Chicago, this 10 week course was one of the most interesting and engaging classes that I’ve been a part of. The best aspect of the course was how involved everyone was, including Dr. Mason and her student assistants. The lectures were well organized with weekly quizzes and corresponding lab videos (which included sheep brain dissection among many other things) and discussions related to current news revolving around neurobiology.

Coursera neurobio 2014
Statement of Accomplishment

It is motivating to be a part of a community that takes time out to learn something new. E-learning is an awesome platform to explore diverse subjects along with people from all over the world. It is also a great opportunity to learn from some of the best minds in the respective fields. I am already looking forward to my next course!