Cholesterol crystals activate the lectin complement pathway via ficolin-2 and mannose-binding lectin: Implications for the progression of atherosclerosis

Katrine Pilely, Anne Rosbjerg, Ninette Genster, Peter Gal, Gabor Pal, Bente Halvorsen, Sverre Holm, Pal Aukrust, Siril Skaret Bakke, Bjørnar Sporsheim, Ingunn Nervik, Nathalie Niyonzima, Emil D. Bartels, Gregory L. Stahl, Tom Eirik Mollnes, Terje Espevik, Peter Garred

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Abstract

Cholesterol crystals (CC) play an essential role in the formation of atherosclerotic plaques. CC activate the classical and the alternative complement pathways, but the role of the lectin pathway is unknown.We hypothesized that the pattern recognition molecules (PRMs) fromthe lectin pathway bind CC and function as an upstreaminnate inflammatory signal in the pathophysiology of atherosclerosis.We investigated the binding of the PRMs mannose-binding lectin (MBL), ficolin-1, ficolin-2, and ficolin-3, the associated serine proteases, and complement activation products to CC in vitro using recombinant proteins, specific inhibitors, as well as deficient and normal sera. Additionally, we examined the deposition of ficolin-2 and MBL in human carotid plaques by immunohistochemistry and fluorescence microscopy. The results showed that the lectin pathway was activated on CC by binding of ficolin-2 and MBL in vitro, resulting in activation and deposition of complement activation products. MBL bound to CC in a calcium-dependent manner whereas ficolin-2 binding was calcium-independent. No binding was observed for ficolin-1 or ficolin-3.MBL and ficolin-2 were present in human carotid plaques, and binding of MBL to CC was confirmed in vivo by immunohistochemistry, showing localization of MBL around CC clefts. Moreover, we demonstrated that IgM, but not IgG, bound to CC in vitro and that C1q binding was facilitated by IgM. In conclusion, our study demonstrates that PRMs from the lectin pathway recognize CC and provides evidence for an important role for this pathway in the inflammatory response induced by CC in the pathophysiology of atherosclerosis.

Original languageEnglish
Pages (from-to)5064-5074
Number of pages11
JournalJournal of Immunology
Volume196
Issue number12
DOIs
Publication statusPublished - Jun 15 2016

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Pilely, K., Rosbjerg, A., Genster, N., Gal, P., Pal, G., Halvorsen, B., Holm, S., Aukrust, P., Bakke, S. S., Sporsheim, B., Nervik, I., Niyonzima, N., Bartels, E. D., Stahl, G. L., Mollnes, T. E., Espevik, T., & Garred, P. (2016). Cholesterol crystals activate the lectin complement pathway via ficolin-2 and mannose-binding lectin: Implications for the progression of atherosclerosis. Journal of Immunology, 196(12), 5064-5074. https://doi.org/10.4049/jimmunol.1502595