How is chronic inflammation established?
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By Shubhankar Kulkarni on Aug 18, 2020
 Pahwa R, Goyal A, Bansal P, Jialal I. Chronic Inflammation [Internet]. StatPearls. 2020. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29630225
 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
Trained immunity via epigenetic reprogramming of the immune cells
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  leading to the formation of foam cells.  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.  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.  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
by Apoorva Kulkarni on Aug 18, 2020