Artistic Rendering of a Cytokine: 11 April 2018 www.scientificanimations.com
Microscopic proteins, known as cytokines, are the master-coordinators behind a multitude of vital operations in the body. From stitching up a scraped knee, to forging an aching fever, to even activating blood assembly—cytokines are the regulatory bodies behind growth and repair, the immune system and inflammation, as well as cell division. Although these immune communicators are well versed in fighting off infection, mounting evidence has demonstrated their fluency in the nervous system’s language: including the development of mental illnesses.
However, cytokines function in a highly sensitive regulatory harmony within our bodies. One tiny miscalculation may result in a dysfunction: an overproduction or underproduction of cytokines, particularly those that interact with immune cells, can send the body into disarray. Although cytokines are crucial to the immune response, these miniature communicators transform into harmful vandals when they overwhelm the body. And when they fail to make an appearance, their absence, too, unleashes an assortment of issues.
Pro-inflammatory cytokines, an important component of the immune system, help dispel pathogens during infection—in the short term. But when they linger in the body, smothering it with chronic inflammation, they trigger widespread dysfunction through complex biological pathways.
Cytokines bridge the gaps in the bigger picture of the body’s functioning: they tell the immune system what substances in the body are foreign, and should be marked for destruction. They signal when cells should divide. However, if these important organizers of the body go haywire, we experience some major misdirection.
An example of this incompetent signaling, chronic inflammation, can provoke life-threatening complications, including heart disease, diabetes, arthritis, and even cancer. Pro-inflammatory cytokines’ overabundance during chronic inflammation in cancer, for example, can induce cell production and alter cell survival for the worse. By modifying how cells divide, cytokines transform cells in ways that render them cancerous: proliferating out of control.
Cytokines are impressively effective at altering cell-functioning, such as their potential to mutate healthy cells into ones with cancer. Although the inflammation theory of disease is well-documented and explored for a multitude of disorders, a lesser-known role of cytokines is their influence on the brain: particularly in psychological disorders. Dysfunctional cytokines can manifest in a dysfunctional mind—including disorders such as depression, anxiety, bipolar, and even PTSD.
Cytokines can induce mental dysfunction by altering neural communication, as well as glial communication, both of which are intrinsic to mental illnesses. Although they command cell-signaling through many pathways, one route by which cytokines veer the brain towards psychopathology (a mental or behavioral disorder) is through changing neurotransmitter functioning. Neurotransmitters are chemical signals that direct neuron firing, and, in excess or deficiency, can lead to mental disorders.
Once a cytokine’s signal reach the brain, it can influence the synthesis, release, and reuptake of neurotransmitters including serotonin, dopamine, and norepinephrine. These neurotransmitters are especially critical in the development of depression, anxiety disorders, bipolar, and schizophrenia: some of the most common mental illnesses.
Swiergiel and colleagues have tested these theories about cytokines and psychopathology through experiments assessing cytokines’ effect on mental dysfunction through mice studies, and found that administering IL-1b (an inflammatory cytokine known as interleukin 1 beta) in mice can induce increased anxiety reactions when exploring an open field, or in a maze.
By inducing an artificial immune dysfunction, we are able to show how real immune dysfunction can alter brain functioning. In this case, these cytokines drastically transformed how the mice responded to their environment: rendering neutral environments threatening, and foreign environments even more daunting.
Further, in human studies, researchers such as Chang and colleagues have found elevated pro-inflammatory cytokine levels in patients with schizophrenia and those with depression, as well as reduced anti-inflammatory cytokine levels. This finding implies that an imbalance in cytokine concentrations–which can be induced by a variety of factors, including diet, environmental pollutants, obesity, or stress–can play a critical role in the development of anxiety disorders, schizophrenia, and depression.
Additionally, recent research by the Lysle Lab at UNC Chapel Hill has shown that SEFL (stress-enhanced fear learning, a rat model of PTSD) will not develop after a stressful event without the release of IL-1b from the hippocampus, a brain region that stores memories.
This evidence implies that IL-1b, an inflammatory cytokine, is essential to PTSD development.
When taking a closer look at the role of cytokines in PTSD, we can see that IL-1b increases the hippocampal neurons’ activity—altering how the hippocampus stores memories long term. IL-1b may change memory storage by stripping contextual details from a stressful event: leaving only the event’s fear, and rendering both animals and humans hypersensitive to stress.
IL-1b’s role in PTSD represents a major breakthrough in neuroimmunology. This evidence holds promising new treatments, focused on cytokine manipulation, to target immunologic dysfunction in psychiatric disorders.
In fact, in rat studies, Jones and colleagues have started to examine these possible treatments for PTSD. For example, these researchers have prevented the development of SEFL, in mice by inhibiting IL-1b expression through morphine injections, and through injections of IL-1ra, which is the antagonist of IL-1b.
Antagonists bind to IL-1b receptor sites, and prevent IL-1b from acting upon the brain. Evidence that IL-1b inhibition is associated with lower risk of PTSD is also echoed on the battlefield: studies show that soldiers that are administered morphine (which inhibits IL-1b) 48 hours to 72 hours after trauma have lower rates of PTSD.
These findings demonstrate that IL-1b signaling is crucial to SEFL development, and therefore, should be a target of new PTSD treatments. Additionally, other studies have located brain regions and cell types where these cytokines are produced, finding that astrocytes primarily manufacture the cytokines implicated in SEFL. Not only does this evidence demonstrate one way astrocyte signaling may affect complex behavior, but by specifying astrocytes as IL-1b’s primary source, researchers are able to create astrocyte specific manipulations to inhibit IL-1b.
In fact, researchers can manipulate astrocytes to inhibit IL-1b with chemogenetic technologies. These technologies are valuable tools that can specifically target certain neuronal signaling, such as the way that astrocytes release cytokines, one of them being a technology called DREADD (Designer Receptors Exclusively Activated by Designer Drugs). In the Lysle Lab, researchers engineered DREADDs to specifically activate inhibitory signaling in dorsal hippocampal astrocytes, in turn, suppressing the release of IL-1b. In rats, astrocyte-specific manipulation can inhibit SEFL.
This research gives us new insight into the complex and daunting inner workings of the human mind, and advances our understanding of psychopathology development. By understanding cytokines in anxiety, depression, and PTSD, we are one step closer to solving an issue that plagues millions of people.
Further, this research confirms our understanding that the origins of abnormal functioning are chaotically intricate: cytokines do not just have one purpose, just as dysfunction does not have one source. We are constantly untangling the interconnected relationships between our bodily systems, as seen in the intertwinedness of the immune system and the nervous system.
An adequate level of cytokines will help your body heal from a scrape or cold: while an overabundance may contribute to cancer or depression. Our brain’s functioning, which takes place before our eyes. is truly more unknown and misunderstood than the cosmos.
By: L. Adams
Chang, T.-T., & Yen, Y.-C. (2010). Cytokines and Major Psychiatric Disorders. Taiwanese Journal of Psychiatry, 24(4 ), 257–268.
Jones, M. E., Lebonville, C. L., Barrus, D., & Lysle, D. T. (2014). The Role of Brain Interleukin-1 in Stress-Enhanced Fear Learning. Neuropsychopharmacology, 40(5), 1289–1296. doi: 10.1038/npp.2014.317
Jones, M. E., Lebonville, C. L., Paniccia, J. E., Balentine, M. E., Reissner, K. J., & Lysle, D. T. (2018). Hippocampal interleukin-1 mediates stress-enhanced fear learning: A potential role for astrocyte-derived interleukin-1β. Brain, Behavior, and Immunity, 67, 355–363. doi: 10.1016/j.bbi.2017.09.016
Roth, B. L. (2016). DREADDs for Neuroscientists. Neuron, 89(4), 683–694. doi: 10.1016/j.neuron.2016.01.040
Swiergiel, A. H., & Dunn, A. J. (2007). Effects of interleukin-1β and lipopolysaccharide on behavior of mice in the elevated plus-maze and open field tests. Pharmacology Biochemistry and Behavior, 86(4), 651–659. doi: 10.1016/j.pbb.2007.02.010
“3D medical animation still of Cytokines that are important in cell signaling.” Scientific Animations, www.scientificanimations.com,11 April 2018