Brainstorming session

How is chronic inflammation established?

Image credit: NCBI

Shubhankar Kulkarni Aug 18, 2020

[1]Pahwa R, Goyal A, Bansal P, Jialal I. Chronic Inflammation [Internet]. StatPearls. 2020. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29630225

[2]Foissac M, Javelle E, Ray S, Guérin B, Simon F. Post-Chikungunya Rheumatoid Arthritis, Saint Martin. Emerg Infect Dis [Internet]. 2015 Mar;21(3):530–2. Available from: http://wwwnc.cdc.gov/eid/article/21/3/14-1397_article.htm

inflammation

Creative contributions

Anti-inflammatory gene therapies/immunization

Andre Pelzmann Nov 26, 2020

[1]Hosseini A, Estiri H, Akhavan Niaki H, Alizadeh A, Abdolhossein Zadeh B, Ghaderian SMH, Farjadfar A, Fallah A. Multiple Sclerosis Gene Therapy with Recombinant Viral Vectors: Overexpression of IL-4, Leukemia Inhibitory Factor, and IL-10 in Wharton's Jelly Stem Cells Used in EAE Mice Model. Cell J. 2017 Oct;19(3):361-374. doi: 10.22074/cellj.2017.4497. Epub 2017 Aug 19. PMID: 28836399; PMCID: PMC5570402.

Conditioned immune responses may provide benefit

Brett M. Nov 28, 2020

Shubhankar Kulkarni2 months ago

Thank you for your contribution. If this works as beautifully as it sounds, it can be a breakthrough for the treatment of a number of chronic inflammatory diseases and, therefore, longevity.

The brain connection was intuitive since stress increasing inflammation and, thereby, the probability of rheumatoid arthritis and other inflammatory diseases (https://www.everydayhealth.com/wellness/united-states-of-stress/link-between-stress-inflammation/#:~:text=Over%20time%2C%20inflammation%20can%20damage,of%20inflammation%20in%20your%20body.)
In this regard, I would also like to direct you to this TED talk, which explains that the effect of stress on your body is dependent on the way you perceive stress (https://www.ted.com/talks/kelly_mcgonigal_how_to_make_stress_your_friend?language=en#t-64209). If the things in the TED talk work and if what you have presented works, controlling inflammation would be a matter of mental conditioning. The non-pharmacological approaches work the best since they have zero side-effects.

Thank you for providing the physiological evidence of learned immunosuppression.

Brett M.2 months ago

Shubhankar Kulkarni Thank you for the feedback Shubhankar! These are very useful resources in this regard - I will definitely be reviewing the TED talk later. 

As for the effect of stress perception, this is a can interesting area and an area that I have focused on during my Doctoral studies. To compound your points here, psychological stress has been found to stimulate the inflammatory response--specifically, through an elevation in pro- and anti-inflammatory cytokines such as interleukin (IL)-1-beta and IL-6, as well as IL-IL-1Ra and IL-10, respectively (https://www.sciencedirect.com/science/article/abs/pii/S1043466697902908). 

Even more interesting is the evidence demonstrating individual differences in the level of inflammation produced in the body following exposure to psychological stress (https://www.sciencedirect.com/science/article/abs/pii/S0301051109000994#:~:text=3.2.%20Changes%20in%20immune%20and%20endocrine%20parameters%20after,%201.92%20%280.32%29%20%206%20more%20rows%20). In addition, studies have shown that chronic psychological stress can induce a pro-inflammatory state in humans (https://pubmed.ncbi.nlm.nih.gov/12433005/) and emphasize the role of glucocorticoid resistance in this process. Thus, a possible physiological mechanism by which chronic inflammation may arise...

In the context that chronic stress can enhance the inflammatory response, and thus possibly contribute to chronic inflammatory conditions, I wonder if one day, we could utilize individual differences in stress perception to predict vulnerabilities to chronic inflammation in humans. From this, we could target populations to begin "conditioned immunosuppression" as a way to train them to "control" their inflammation in stressful circumstances. That being said, we'd need to disentangle the mechanisms involved in this process of conditioned immunosuppression, but I think we aren't far from doing so.

Lastly, I want to direct your attention to a thought-provoking article about an "evolutionary" aspect of the stress-inflammation link, which I think has very interesting ties to this conversation: http://www.uclastresslab.org/pubs/Slavich_Irwin_PsychBull_2014.pdf#:~:text=From%20Stress%20to%20Inflammation%20and%20Major%20Depressive%20Disorder%3A,among%20the%20strongest%20proximal%20risk%20factors%20for%20depression.

Shubhankar Kulkarni2 months ago

Brett Melanson Thank you for sharing the papers!
What I gather from these papers is that chronic stress may lead to chronic inflammation. The constant upregulation of stress elicits a constant inflammatory response. Figure 1 here (http://www.uclastresslab.org/pubs/Slavich_Irwin_PsychBull_2014.pdf#:~:text=From%20Stress%20to%20Inflammation%20and%20Major%20Depressive%20Disorder%3A,among%20the%20strongest%20proximal%20risk%20factors%20for%20depression) explains the difference between historical and modern stress very clearly. The rise in the pro-inflammatory cytokines is always anticipatory. Historical stress anticipates physical harm (injury). Inflammatory molecules are required at the site of injury, both as immune molecules and to illicit the repair pathway. These molecules are secreted before the injury. Modern stress also leads to the secretion of the anticipatory inflammatory molecules. However, there is no "physical" threat, which leads to the build-up of these pro-inflammatory molecules. Constant psychological stress leads to a chronic build-up of the pro-inflammatory molecules that now cause more harm than good to the body.

It is also interesting that the authors here (https://pubmed.ncbi.nlm.nih.gov/12433005/) propose a glucocorticoid-resistance model to explain the impact of stress on inflammatory conditions. The model suggests that chronic stress "diminishes the immune system’s sensitivity to glucocorticoid hormones that normally terminate the inflammatory cascade." I wonder why does chronic stress decreases the sensitivity of the pathway that brings down inflammation when the intuitive way would be to decrease the sensitivity to hormones that increase the inflammation in the first place. The only logical explanation I could think of is that there may not exist many pathways that decrease or avoid generating an inflammatory response. This might be because of the evolutionary advantage organisms had. Stress was usually followed by injury and hence, the need for inflammation. No inflammation upon injury might be more detrimental (in the short run) that inflammation and no injury. I hope this makes sense.

It would be interesting to identify pathways that avoid generating an inflammatory response in the first place and see how they react to stress.