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Is our mean body temperature decreasing and why? What can we learn from it?
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Shubhankar Kulkarni Aug 18, 2020
What is your idea regarding the way inflammation sets in and how can it be eliminated?
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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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Conditioned immune responses may provide benefit
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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Anti-inflammatory gene therapies/immunization
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.
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Trained immunity via epigenetic reprogramming of the immune cells
AK
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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