Neuroinflammation

A common factor in many chronic health problems

Neuroinflammation means inflammation in the nervous system. Emerging evidence suggests it plays a central role in many complex health problems such as chronic pain, fibromyalgia, chronic fatigue, depression, anxiety, and Alzheimer's. This post summarizes some basic information about what it is, why is arises, how it causes pathology, and what we might do to reduce it.

The neuro-immune system

The nervous system and the immune system have distinct functions when viewed from a high-level perspective. The job of the immune system is to fight infections and repair damage, and the job of the nervous system is to process information and coordinate action. But when you look at these systems up close, their actions are densely interconnected, harder to distinguish. This is especially true in the context of pain perception, where they work together to protect the body from tissue damage. In fact, pain scientists often refer to them by one name - the neuro-immune system.

Basic physiology of neuroinflammation

About half the cells in the nervous system are glial cells, which don’t produce electrical impulses like neurons. Instead, they surround neurons, hold them in place, supply nutrients and oxygen, and assist with neurotranmission. In the brain, they can assist with consolidation of memories.

Microglia are immune cells in the central nervous system that actively search for infections or damage, destroying pathogens and removing dead neurons and debris. When active, they create neuroinflammation, mediated by inflammatory cytokines like IL-6, TNFa, prostaglandins, reactive oxgen species, and chemokines (DiSibato 2019). This inflammation serves many useful purposes, like helping to repair tissues, fight infection, and even improve learning and memory. But when it is excessive or chronic, it can cause problems. Like an aggressive police force that attacks innocent citizens, neuroinflammation can damage the tissues it should be protecting, causing injury to neurons, myelin sheaths and the blood-brain-barrier. Damage to the blood-brain-barrier may be especially problematic, because part of its function is to protect the central nervous system from pathogens, toxins and immune cells moving in the periphery of the body. This ensures that local injuries, infections and associated immune system activity does not end up affecting the brain. In the presence of excessive levels of neuroinflammation, the permeability of the blood-brain-barrier can increase, allowing entry to toxins and cytokines that create more inflammation.

For these reasons, neuroinflammation is suspected to play a key role in numerous health conditions. Here’s a brief list.

Chronic pain and fatigue

It is well known that inflammation near the site of any injury makes pain worse. The inflammation sensitizes nociceptors, lowering their firing threshold, and making them more likely to send nociceptive signals towards the brain. Neuroinflammation in the spinal cord and brain has similar effects. A recent paper (Ji 2018) states that neuroinflammation is a powerful driver of chronic and widespread pain, through central sensitization:

Chronic pain is maintained in part by central sensitization, a phenomenon of synaptic plasticity and increased neuronal responsiveness in central pain pathways after painful insults. Accumulating evidence suggests that central sensitization is also driven by neuroinflammation …

a characteristic feature of neuroinflammation is the activation of glial cells, such as microglia and astrocytes, in the spinal cord and brain, leading to the release of pro-inflammatory cytokines and chemokines …

sustained increase of cytokines and chemokines in the CNS also promotes chronic widespread pain that affects multiple body sites. Thus, neuroinflammation drives widespread chronic pain via central sensitization. 

For example, it has been shown that microglia play a role in sensitization of the dorsal horn. Drugs that interfere with the function of microglia have been shown to completely reverse the development of a pain state in animals (Hore 2019).

Inflammation makes the nervous system more sensitive to pain, and also to other unpleasant feelings and “sickness behaviors.” Chronic fatigue syndrome is a condition causing fatigue, malaise, and cognitive problems (often called “brain fog”). Many patients report that symptoms began shortly after a viral infection (Van Elzakker 2019). Researchers suspect that neuroinflammation, caused by peripheral cytokines crossing the blood-brain-barrier, may be a root cause. PET scans have confirmed the presence of excessive neuroinflammation in the brains of chronic fatigue patients (Nakatomi 2018). Similar findings have been made for fibromyalgia patients (Albrecht 2019). Neuroinflammation may be involved in depression as well (Troubat 2020).

Neurodegenerative conditions

Pathological neuroinflammation plays a major role in multiple sclerosis, Parkinson's, ALS, and Alzheimer’s (Kwon 2020).

Causes of neuroinflammation

The following have been identified as potential causes of neuroinflammation:

• trauma to the brain or spinal cord

• bacterial or viral infection

• toxins

• air pollution

• smoking

• obesity

• emotional stress

• alcohol abuse

• insomnia

• aging

• autoimmunity

(Block 2009); (Miller 2104); (Zhu 2012). In perusing this list, we can immediately identify some ways to prevent or possibly reduce neuroinflammation. Most of these are common sense general health precautions that we all know: avoid smoking, don’t drink too much, control your weight, eat a healthy diet, get plenty of sleep and reduce stress. Avoid concussions. Get your vaccinations so you don’t end up with Long Covid or some other post-viral syndrome.

One item on this list that is generally underappreciated is air pollution. Emerging evidence is showing that air pollution is just unbelievably bad for you, with significant effects that are easily measured at moderate levels. Experts estimate that it causes 7 million deaths a year. Long-term exposure causes neuroinflammation, disrupts the blood brain barrier, lowers IQ, and increases the risk of Parkinson's and Alzheimer's.(Block 2009); (Calderón-Garcidueña 2008). I plan to write soon about this topic in more detail, and include some practical suggestions of how to reduce our exposure to air pollution.

What about exercise, the thing that seems so good for so many different conditions, including many of the ones I have listed above? Exercise tends to promote homeostasis and balance in every system in the body, including the immune system, nervous system and the brain. It has been shown to reduce inflammation in the periphery, reduce expression of inflammation cytokines, and reduce proliferation of microglia in the brain (Kohman 2013); (Seo 2019). So yes, exercise is a way to prevent and maybe reduce neuroinflammation.

It should be noted that the above discussion is very simplified and barely scratches the surface of this complex topic. Further, we already know that many of the diseases I mentioned are very hard to treat, even with the interventions I discussed. That being said, knowledge is power, and some knowledge is better than none. Hopefully we can look forward to an increase in the knowledge and power regarding neuroinflammation as research progresses.

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References

1. Albrecht, Daniel S., Anton Forsberg, Angelica Sandstrom, Courtney Bergan, Diana Kadetoff, Ekaterina Protsenko, Jon Lampa, et al. “Brain Glial Activation in Fibromyalgia - a Multi-Site Positron Emission Tomography Investigation.” Brain, Behavior, and Immunity 75 (January 2019): 72–83. https://doi.org/10.1016/j.bbi.2018.09.018.

2. Block, Michelle L., and Lilian Calderón-Garcidueñas. “Air Pollution: Mechanisms of Neuroinflammation and CNS Disease.” Trends in Neurosciences 32, no. 9 (September 2009): 506–16. https://doi.org/10.1016/j.tins.2009.05.009.

3. Calderón-Garcidueñas L, Solt AC, Henríquez-Roldán C, Torres-Jardón R, Nuse B, Herritt L, Villarreal-Calderón R, Osnaya N, Stone I, García R, Brooks DM, González-Maciel A, Reynoso-Robles R, Delgado-Chávez R, Reed W. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults. Toxicol Pathol. 2008 Feb;36(2):289-310. doi: 10.1177/0192623307313011. Epub 2008 Mar 18. PMID: 18349428.

4. DiSabato, Damon J., Ning Quan, and Jonathan P. Godbout. “Neuroinflammation: The Devil Is in the Details.” Journal of Neurochemistry 139, no. S2 (2016): 136–53. https://doi.org/10.1111/jnc.13607.

5. Hore, Zoe, and Franziska Denk. “Neuroimmune Interactions in Chronic Pain – An Interdisciplinary Perspective.” Brain, Behavior, and Immunity 79 (July 2019): 56–62. https://doi.org/10.1016/j.bbi.2019.04.033.

6. Kohman RA, Bhattacharya TK, Wojcik E, Rhodes JS (September 2013). "Exercise reduces activation of microglia isolated from hippocampus and brain of aged mice". Journal of Neuroinflammation. 10: 114. doi:10.1186/1742-2094-10-114. PMC3848770. PMID24044641.

7. Kwon HS, Koh SH. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 2020 Nov 26;9(1):42. doi: 10.1186/s40035-020-00221-2. PMID: 33239064; PMCID: PMC7689983.

8. Miller, Alyson A., and Sarah J. Spencer. “Obesity and Neuroinflammation: A Pathway to Cognitive Impairment.” Brain, Behavior, and Immunity 42 (November 1, 2014): 10–21. https://doi.org/10.1016/j.bbi.2014.04.001.

9. Nakatomi Y, Kuratsune H, Watanabe Y. [Neuroinflammation in the Brain of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]. Brain Nerve. 2018 Jan;70(1):19-25. Japanese. doi: 10.11477/mf.1416200945. PMID: 29348371.

10. Ji, Ru-Rong, Andrea Nackley, Yul Huh, Niccolò Terrando, and William Maixner. “Neuroinflammation and Central Sensitization in Chronic and Widespread Pain.” Anesthesiology 129, no. 2 (August 2018): 343–66. https://doi.org/10.1097/ALN.0000000000002130.

11. Matsuda, Megumi, Yul Huh, and Ru-Rong Ji. “Roles of Inflammation, Neurogenic Inflammation, and Neuroinflammation in Pain.” Journal of Anesthesia 33, no. 1 (February 2019): 131–39. https://doi.org/10.1007/s00540-018-2579-4.

12. Seo, Dae-Yun, Jun-Won Heo, Jeong Rim Ko, and Hyo-Bum Kwak. “Exercise and Neuroinflammation in Health and Disease.” International Neurourology Journal 23, no. Suppl 2 (November 30, 2019): S82-92. https://doi.org/10.5213/inj.1938214.107.

13. VanElzakker, Michael B., Sydney A. Brumfield, and Paula S. Lara Mejia. “Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods.” Frontiers in Neurology 9 (2019): 1033. https://doi.org/10.3389/fneur.2018.01033.

14. Zhu, Biao, Yuanlin Dong, Zhipeng Xu, Heinrich S. Gompf, Sarah A.P. Ward, Zhanggang Xue, Changhong Miao, Yiying Zhang, Nancy L. Chamberlin, and Zhongcong Xie. “Sleep Disturbance Induces Neuroinflammation and Impairment of Learning and Memory.” Neurobiology of Disease 48, no. 3 (December 2012): 348–55. https://doi.org/10.1016/j.nbd.2012.06.022.