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What is your idea regarding the way inflammation sets in and how can it be eliminated?

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Shubhankar Kulkarni
Shubhankar Kulkarni Aug 18, 2020
How is chronic inflammation established? What experiments can we perform to address the issue?

Chronic inflammation is a slow, long-term inflammation lasting for periods ranging from several months to years. Diseases due to chronic inflammation are the most significant cause of death. These include diabetes, cardiovascular diseases, arthritis, chronic obstructive pulmonary disorder, and different allergies.

It is known that chronic inflammation is induced due to reasons like infections, an irritant-like foreign material, etc. However, sometimes, the inflammation persists even after these causes are treated (for example, joint pain after Chikungunya infection).

Before we find ways to eliminate it, we need to come up with a theoretical understanding of the mechanism. It seems like inflammation causes a positive feedback loop. How can we better explain this? Can you think of any other mechanism?

[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

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Anti-inflammatory gene therapies/immunization

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Andre Pelzmann
Andre Pelzmann Nov 26, 2020
Experimental anti-inflammatory gene therapies will be part of the main treatments against inflammation shortly. I would like to present some examples as case study-like evidence. For example, NF-Kappa B (a transcription factor, which plays a key role in inflammatory reactions) is a target for such an intervention.
Another example is the anti-inflammatory gene therapy in sclerosis multiplex. In this case, the overexpression of interleukin-4 (IL-4), IL-10, and leukemia inhibitory factor (LIF) in Wharton’s jelly stem cells (WJSCs) in the experimental autoimmune encephalomyelitis (EAE) mice model have been showing promising results.
Also, a possible opportunity for the various vaccinations as non-genetic intervention opportunities. For example, the vaccination by LDL cholesterol as antigen could reduce the effects of atherosclerosis.

[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

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Brett M.
Brett M. Nov 28, 2020
In Psychology, there is a concept known as classical conditioning. Through this process, there is a stimulus in the environment that elicits a specific response. When that stimulus is paired with another stimulus that typically does not elicit a response, over time, the secondary "neutral" stimulus elicits a response on its own without the presence of the primary response-eliciting stimulus.

To put this another way, think of the classical experiment involving Pavlov's dogs. Pavlov would present food to dogs, and they would salivate upon receiving the food. Then, he began to pair the presentation of food with the ringing of a bell. After many "pairings", he began to notice that if he rang the bell without any food presented, the dogs would still salivate as if there was food. This led Pavlov to believe that the bell took on characteristics of the food, and conditioned the dogs to think of food when they hear the bell. This salivation response to a ringing bell was termed the conditioned response.

Now, this becomes an interesting concept when thinking of chronic inflammation. There is a large percentage of behaviors in our lives that are the result of conditioning processes, but this concept is not limited strictly to behavior. There is now evidence demonstrating that an immune response can actually be conditioned! In these studies, they show that pairing the immunosuppressive drug, cyclosporine A with a sweetened water solution causes the sweetened solution to have immunosuppressing effects upon re-exposure in absence of cyclosporine A.

This has critical implications for those who are on long-term therapy with anti-inflammatory drugs (e.g., NSAIDs), as it has been proposed that long-term use of these compounds can promote compensatory pro-inflammatory responses in the host. This simply means that after long-term use with NSAIDs like Tylenol or Aspirin, it is possible that the host immune response begins to compensate for the continued immunosuppression of these drugs by upregulating pro-inflammatory mechanisms.

Moreover, the conditioned immunosuppressive effects in rats were found to be dependent on the insular cortex--a brain region analogous to the human insula which is responsible for regulating mood and emotion, among other processes.

An important thing to note here is that anti-inflammatory drugs act to reduce inflammation at the level of the immune cells, whereas the conditioned immunosuppression appears to be dependent on specific regions in the brain, implying a cognitive component of this suppression of inflammation. And, the compensatory response may be occurring at the level of the immune cell, suggesting that conditioned immunosuppression would not risk this compensatory effect. More research would be needed to understand the long-term effects of conditioned immunosuppression in this circumstance, but it certainly presents a promising approach for these types of bodily conditions.

As a brief thought experiment, it would be interesting if health officials incorporated this idea of conditioned immunosuppression in their treatment regimen, by developing a protocol to pair the immunosuppressive drug with a sweetened drink. Then, as they continue to pair the drug with the drink, the patient would gradually wean off of the drug and maintain intake of the paired drink, which may allow the patient's immune system to avoid the compensatory response to long-term anti-inflammatory drug use and slowly begin depending on the conditioned immunosuppression triggered by the brain.


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Shubhankar Kulkarni
Shubhankar Kulkarni8 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.
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Brett M.
Brett M.8 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.
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Shubhankar Kulkarni
Shubhankar Kulkarni8 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.

Trained immunity via epigenetic reprogramming of the immune cells

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AK
Apoorva Kulkarni Aug 18, 2020
In atherosclerosis, monocytes enter into the blood vessel wall. It was shown that mice deficient in monocyte chemokine signaling have less atherosclerosis. [1-3] Monocytes differentiate into macrophages and engulf oxidized low-density lipoprotein (oxLDL) particles [4] leading to the formation of foam cells. [5] A study reported that stimulation of monocytes with oxidized low-density lipoprotein (oxLDL) induced a long-lasting pro-inflammatory phenotype via epigenetic reprogramming. This process is called trained immunity. After exposure of isolated human monocytes to oxLDL for 24 hours, the monocytes showed increased mRNA and protein expression of pro-inflammatory molecules like interleukin-6, interleukin-18, interleukin-8, tumor necrosis factor-α, monocyte chemoattractant protein 1, and matrix metalloproteinase 2 and 9, after toll-like receptor 2 and 4 stimulation. Enhanced foam cell formation was also observed. They authors also demonstrated increased trimethylation of lysine 4 at histone 3 in promoter regions of the above-mentioned pro-inflammatory molecules, which increased their expression. Also, pre-treating the monocytes with a histone methyltransferase inhibitor prevented this oxLDL-induced proinflammatory phenotype. [6] Similarly, peripheral blood mononuclear cells (PBMCs) harvested from patients with gout showed a higher production of interleukin (IL)-1β and IL-6 when stimulated with Toll-like receptor (TLR)2 or TLR4 ligands. Pro-inflammatory cytokine production increased when cells from healthy subjects were pre-treated with uric acid. This was also associated with a down-regulation of anti-inflammatory cytokines. These effects were inhibited when a histone methyltransferase inhibitor was added, suggesting epigenetic modulation. [7] These studies suggest that at least one of the ways to establish chronic inflammation is by reprogramming the immune cells to produce increased quantities of pro-inflammatory cytokines. References: 1. Braunersreuther V, Zernecke A, Arnaud C, Liehn EA, Steffens S, Shagdarsuren E, et al. Ccr5 But Not Ccr1 Deficiency Reduces Development of Diet-Induced Atherosclerosis in Mice. Arterioscler Thromb Vasc Biol [Internet]. 2007 Feb;27(2):373–9. Available from: https://www.ahajournals.org/doi/10.1161/01.ATV.0000253886.44609.ae 2. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature [Internet]. 1998 Aug;394(6696):894–7. Available from: http://www.nature.com/articles/29788 3. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, et al. Absence of Monocyte Chemoattractant Protein-1 Reduces Atherosclerosis in Low Density Lipoprotein Receptor–Deficient Mice. Mol Cell [Internet]. 1998 Aug;2(2):275–81. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1097276500801392 4. Kunjathoor V V., Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S, et al. Scavenger Receptors Class A-I/II and CD36 Are the Principal Receptors Responsible for the Uptake of Modified Low Density Lipoprotein Leading to Lipid Loading in Macrophages. J Biol Chem [Internet]. 2002 Dec 20;277(51):49982–8. Available from: http://www.jbc.org/lookup/doi/10.1074/jbc.M209649200 5. Moore KJ, Tabas I. Macrophages in the Pathogenesis of Atherosclerosis. Cell [Internet]. 2011 Apr;145(3):341–55. Available from: https://linkinghub.elsevier.com/retrieve/pii/S00928674110042235. 6. Bekkering S, Quintin J, Joosten LAB, van der Meer JWM, Netea MG, Riksen NP. Oxidized Low-Density Lipoprotein Induces Long-Term Proinflammatory Cytokine Production and Foam Cell Formation via Epigenetic Reprogramming of Monocytes. Arterioscler Thromb Vasc Biol [Internet]. 2014 Aug;34(8):1731–8. Available from: https://www.ahajournals.org/doi/10.1161/ATVBAHA.114.303887 7. Crișan TO, Cleophas MCP, Oosting M, Lemmers H, Toenhake-Dijkstra H, Netea MG, et al. Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Ann Rheum Dis [Internet]. 2016 Apr;75(4):755–62. Available from: http://ard.bmj.com/lookup/doi/10.1136/annrheumdis-2014-206564

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