Complement activation by cholesterol crystals triggers a subsequent cytokine response.
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.
Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway; MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, SE1 9RT London, UK.
Nathalie
N
Niyonzima
Research Institute of Internal Medicine, University Hospital Rikshospitalet, 0424 Oslo, Norway; K.J. Jebsen Inflammation Research Centre, University of Oslo, 0318 Oslo, Norway.
Bente
B
Halvorsen
Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
Bjørnar
B
Sporsheim
Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Peter
P
Garred
Research Institute of Internal Medicine, University Hospital Rikshospitalet, 0424 Oslo, Norway; K.J. Jebsen Inflammation Research Centre, University of Oslo, 0318 Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, 0424 Oslo, Norway; Institute of clinical medicine, University of Oslo, 0424 Oslo, Norway.
Pål
P
Aukrust
Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway; K.J. Jebsen Inflammation Research Centre, University of Oslo, 0318 Oslo, Norway; Institute of Clinical Medicine and K.J. Jebsen TREC University of Tromsø, 9037 Tromsø, Norway; Research Laboratory, Nordland Hospital, 8092 Bodø, Norway; Department of Immunology, Oslo University Hospital Rikshospitalet, 0027 Oslo, Norway.
Tom Eirik
TE
Mollnes
Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway. Electronic address: terje.espevik@ntnu.no.
Terje
T
Espevik
D000818:Animals; D050197:Atherosclerosis / Q000276:immunology*; D016893:Carotid Stenosis / Q000276:immunology*; D002784:Cholesterol / Q000009:adverse effects* / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007249:Inflammation / Q000276:immunology
D016207:Cytokines; D002784:Cholesterol
Atherosclerosis; Cholesterol crystals; Complement; Inflammasome; Interleukin-1beta