Inflamed Body, Distressed Mind: The Mast Cell–Mental Health Link

Mast Cell Activation Syndrome has gained a lot of attention in the past several years as more researchers have shined a light on this and a cluster of commonly accompanying disorders.  In 2020, the NIH performed a thorough review of the literature and released updated recommendations that have been changing the way that we view, treat, and conceptualize the disorder. Our last post covered ways in which inflammation can lead to changes in the brain that are experienced as depression, but today we want to consider interconnectedness of the mast cell-mental health link.

What are mast cells?

Mast cells are large cells that are integral to your immune system. They are found in nearly every tissue of the body and, as part of normal physiology, their job is to burst open in response to environmental triggers and share their chemicals with nearby tissues. This process is called degranulation. These chemicals trigger a cascade of reactions that lead to inflammation in the affected tissue.  While this may sound like a violent process you wouldn’t want to have happened to you, it’s actually quite important for healing and protection. An example of this happening is when you eat that five day old chicken that your wife warned you about, and then find yourself in a non-consensual relationship with the toilet for the next 24 hours. Another example is when you fall and sprain your ankle, resulting in swelling for the next few days. 

While both of these examples are uncomfortable, they highlight a very important process: inflammation under normal conditions is the process by which we heal. The problem is when these cells become over-sensitized to a single trigger, as in the case of a person with an allergy, or extremely over-sensitized to many unpredictable triggers, as is the case with MCAS. This can lead to unnecessary and repeated triggering of the mast cells where the individual becomes highly inflamed and sensitized to their environment. 

Right, but what does this have to do with your brain?

Among the inflammatory chemicals that are released in the degranulation process also lie many important neuropeptides and other hormonal mediators. These include:

• Dopamine

• Histamine

• 5-Hydroxytryptamine (5-HT, serotonin)

• ACTH

• Corticotropin-Releasing Hormone

• Endorphins

• Melatonin

• Acetylcholine

• GABA

• Glutamate

• Opioid Peptides

• And more

Not only are these released during degranulation, but there is a close interplay between these neurotransmitters and mast cells that can range from direct activation of degranulation to enhancement or even repression of responses. (Xu et. al 2020) The exact mechanism of each of these mediators on the brain is only understood with varying degrees of depth, but research continues to emerge. 

The Plot Thickens

What is better understood is that when many of these neuropeptides are released into the peripheral tissue they can lead to varied symptoms including headaches, hypotension, pruritus, inflammation, fatigue, flushing, bronchoconstriction and more. As a result these mast-cell derived mediators have been implicated in many different disorders from chronic fatigue syndrome to fibromyalgia to obesity and autism spectrum disorder (ASD), and more. 

The connection between mastocytosis and neurodevelopmental disorders is of particular interest and has been better studied than many of the other diseases that have been implicated as correlated to mast cell degranulation. Children with mastocytosis have a 10-fold higher risk of developing ASD, and allergic symptoms have been significantly correlated with ASD severity (Theoharides, 2009). The specific role of inflammatory mediators in the brain is still poorly understood, unfortunately. But they are known to be involved in neuroinflammation, brain disorders. They are said to be the “immune gateway to the brain” due to the fact that they regulate permeability of the blood brain barrier. Histamine and tryptase (mediators both released by mast cells) can activate brain cells called microglia leading to secretion of pro-inflammatory markers that are known to be increased in children with ASD (Theohardies et. al 2019). 

While there has been more research done on ASD and the connection to inflammation, it would be a gross simplification to imply that this is the only mental health disorder impacted by inflammation. While we don’t fully understand the pathways by which the brain is affected by inflammation, clinically we see that people who are struggling with all the previously mentioned disorders almost universally also struggle with anxiety, depression, brain fog, hormonal mood shifts, sleep disorders, and in some cases even psychotic symptoms. This isn’t surprising as we consider the influence over neurotransmitters previously highlighted in this article. 

Bringing It All Together

The intricate relationship between mast cells and neuropsychiatric health is becoming increasingly clear. As discussed, mast cells, vital components of our immune system, release a complex array of inflammatory chemicals, neuropeptides, and hormonal mediators upon degranulation. While this process is essential for healing, an over sensitization of mast cells, as seen in MCAS, can lead to chronic inflammation and a host of varied symptoms, extending far beyond physical discomfort.

Crucially, the substances released by mast cells, including dopamine, histamine, serotonin, and various neuropeptides, have direct and significant influences on brain function. This interplay can range from direct activation of degranulation to modulation of neuronal responses. The impact of these mediators on the brain is evident in their implication in conditions like chronic fatigue syndrome, fibromyalgia, obesity, and autism spectrum disorder. The heightened risk of ASD in children with mastocytosis and the correlation between allergic symptoms and ASD severity underscore the profound connection.

While the specific mechanisms by which inflammation impacts mental health are still being fully elucidated, the clinical observation of anxiety, depression, brain fog, hormonal mood shifts, sleep disorders, and even psychotic symptoms in individuals with inflammatory conditions highlights the widespread neurological consequences. Understanding this complex interplay between the immune system and psychiatric disorders is paramount for developing comprehensive and effective treatment strategies that address the whole person. This emerging field of research offers promising avenues for improving the lives of those affected by inflammatory disorders and their associated neuropsychiatric manifestations.

Considering possible inflammatory processes is integral to our process at Something Human. Whole person care means truly listening to your unique story and helping you navigate the complexities of your health. If you're ready to explore how a whole-person approach can make a difference in your life, we invite you to connect with us. Reach out today to schedule an appointment and begin your journey toward lasting well-being.

Rachel Ward, PMHNP-BC is the medical director and founder of Something Human Mental Health and believes strongly in holistic, well rounded approach to care.

References:

Krystel-Whittemore M., Dileepan KN., Wood JG. (2016) Mast Cell: A Multi-Functional Master Cell. Front Immunol.6(6), 620. doi: 10.3389/fimmu.2015.00620. 

Theoharides, T. C. (2009). Autism spectrum disorders and mastocytosis. International Journal of immunopathology and pharmacology, 22(4), 859-865.

Theoharides TC, Tsilioni I, Ren H. (2019) Recent advances in our understanding of mast cell activation - or should it be mast cell mediator disorders? Expert Rev Clin Immunol.(6):639-656. doi: 10.1080/1744666X.2019.1596800. 

Xu, H., Shi, X., Li, X., Zou, J., Zhou, C., Liu, W., Shao, H., Chen, H., & Shi, L. (2020). Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review. Journal of neuroinflammation, 17(1), 356. https://doi.org/10.1186/s12974-020-02029-3