Blogger: Siril S. Bakke, PhD/Post doc, Centre of Molecular Inflammation Research (CEMIR)
Cardiovascular disease resulting from atherosclerosis is one of the most common causes of death worldwide. Our new study reveals molecular mechanisms behind how a cyclic sugar reduces inflammation on the surface of cholesterol crystals.
Inflammation and the activation of the innate immune system, through the complement system, play a crucial role in the development of atherosclerosis. Cholesterol crystals are triggers of these processes as the disease develops. The complement system is a defense system that alters the surface of foreign material so that immune cells can engulf it for destruction.
Cholesterol crystals (CC) initiate inflammatory responses in immune cells called macrophages – this is inhibited by the sugar molecule cyclodextrin (BCD). CC may be recognised by the innate immune system through the complement system (components represented here as shperes and immuno-complexes as stars) and be engulfed by a macrophage. This leads to the transcription of pro-inflammatory genes and cytokine release, thus, causing local inflammation. When the sugar cyclodextrin is present it coats the CC and prevents uptake of the CC by the macrophage. Cyclodextrin can also dissolve CC andwill also enter into the macrophage and activate the transcription factor Liver X receptors and this may lead to a decrease in transcription and release of the pro-inflammatory factors.
Scientists from Centre of Molecular Inflammation Research (CEMIR) at NTNU in Trondheim together with national and international collaborators from University of Bonn, Copenhagen and Oslo have recently published a new paper in Journal of Immunology that shows that a sugar, called 2-hydroxypropyl-β-cyclodextrin (cyclodextrin), reduces inflammation caused by cholesterol crystals.
This is a follow up study from last year, when we found that cyclodextrin reduces and prevents formation of atherosclerotic plaques in mice, as well as dissolve cholesterol crystals. Cyclodextrin also had anti-inflammatory effects on cells in atherosclerotic plaques from humans. That study promoted large publicity, making patients aware of the new basic results (see link for article in Gemini and Science Daily below).
Patients from all over the world contacted us to be a part of our study. As this was a basic research project we had to turn them down, however, if funding is available there is a great potential for a thorough clinical research project to see if treatment with cyclodextrin can be beneficial for the patients.
We still want to know more about the molecular mechanisms behind how cyclodextrin reduce the inflammation. Our follow-up study shows that cyclodextrin binding to the surface of cholesterol crystals reduces complement activation, and the entering of cholesterol crystals in the immune cells. Thereby, cyclodextrin prevents induction of inflammation.
Both our studies suggest that cyclodextrin can be a promising therapeutic approach for treating atherosclerosis because it inhibits inflammation, and thereby have the potential in lowering the deaths caused by atherosclerosis.
References:
- Cyclodextrin Reduces Cholesterol Crystal-Induced Inflammation by Modulating Complement Activation. Bakke SS/Aune MH, Niyonzima N/Pilely K, Ryan L, Skjelland M, Garred P, Aukrust P, Halvorsen B, Latz E, Damås JK, Mollnes TE, Espevik T. J Immunol. 2017 Aug 30. pii: ji1700302. doi: 10.4049/jimmunol.1700302.
- Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Zimmer S/Grebe A, Bakke SS, Bode N, Halvorsen B, Ulas T, Skjelland M, De Nardo D, Labzin LI, Kerksiek A, Hempel C, Heneka MT, Hawxhurst V, Fitzgerald ML, Trebicka J, Björkhem I, Gustafsson JÅ, Westerterp M, Tall AR, Wright SD, Espevik T, Schultze JL, Nickenig G, Lütjohann D, Latz E. Sci Transl Med. 2016 Apr 6;8(333):333ra50. doi: 10.1126/scitranslmed.aad6100.
- Ny behandling av åreforkalkning med sukkerstoff. Gemini (in Norwegian)
- New hope for treating atheriosclerosis. Science Daily.