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Region Hovedstaden - en del af Københavns Universitetshospital
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Complement activation by cholesterol crystals triggers a subsequent cytokine response

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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  • Nathalie Niyonzima
  • Bente Halvorsen
  • Bjørnar Sporsheim
  • Peter Garred
  • Pål Aukrust
  • Tom Eirik Mollnes
  • Terje Espevik
Vis graf over relationer

In the host a diverse collection of endogenous danger signals is constantly generated consisting of waste material as protein aggregates or crystalline materials that are recognized and handled by soluble pattern recognition receptors and phagocytic cells of the innate immune system. These signals may under certain circumstances drive processes leading to adverse inflammation. One example is cholesterol crystals (CC) that accumulate in the vessel wall during early phases of atherogenesis and represent an important endogenous danger signal promoting inflammation. CC is recognized by the lectin- and classical pathways of the complement system resulting in activation of C3 and C5 with release of inflammatory mediators like the potent C5a fragment. Complement activation by CC leads to crosstalk with the NLRP3 inflammasome-caspase-1 pathway and production of IL-1β. Neutralization of IL-1β may have beneficial effects on atherosclerosis and a large clinical trial with an IL-1β inhibitor is currently in progress (the CANTOS study). However, upstream inhibition of CC-induced inflammation by using a complement inhibitor may be more efficient in treating atherosclerosis since this will block initiation of inflammation processes before downstream release of cytokines including IL-1β. Another therapeutic candidate can be broad-acting 2-hydroxypropyl-β-cyclodextrin, a compound that targets several mechanisms such as cholesterol efflux, complement gene expression, and the NLRP3 pathway. In summary, emerging evidence show that complement is a key upstream player in the pathophysiology of atherosclerosis and that therapy aiming at inhibiting complement could be effective in controlling atherosclerosis.

OriginalsprogEngelsk
TidsskriftMolecular Immunology
Vol/bind84
Sider (fra-til)43-50
Antal sider8
ISSN0161-5890
DOI
StatusUdgivet - 2017

ID: 49165219