Trained immunity and atherosclerosis

Radboud university medical center, Nijmegen, the Netherlands

 

Research topic

Although the phenomenon of trained innate immunity (TRIM) is undoubtedly beneficial in the context of recurrent infections and vaccination, it might be detrimental in the context of chronic inflammatory disorders that are driven by chronic activation of the innate immune system.

Atherosclerosis is a chronic low-grade inflammatory disease of the arterial wall. Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques, and orchestrate really the initiation, progression, and rupture of atherosclerotic plaques. We propose that the enhanced functional state of trained monocytes can accelerate the development of atherosclerosis. By this mechanism, stimuli that can induce TRIM (e.g. microbial products or endogenous pro-atherogenic compounds) can exert a long-term pro-atherogenic effect.

Our group aims at investigating the role of TRIM in atherogenesis from bench-to-bedside.

In isolated human monocytes, we brief stimulation with various microbial products (e.g. beta-glucan) induces a long-lasting pro-atherogenic phenotype that is characterized by increased production of pro-atherogenic cytokines and chemokines, increased foam cell formation, and increased production of proteases that can result in destabilization of atherosclerotic plaques. Interestingly, TRIM could also be induced by oxidized LDL particles and lipoprotein (a). Monocytes isolated from patients with elevated Lp(a) showed a trained immune phenotype, and this was associated with increased adherence to the vessel wall and increased arterial wall inflammation in vivo. In addition, monocytes isolated from patients with severe established atherosclerosis show a trained immune phenotype, both in terms of cytokine production, as well as in term of metabolic and epigenetic reprogramming.

In the next few years we aim to firmly establish the role of TRIM in the development of atherosclerosis in the context of various traditional and novel cardiovascular risk factors.


Group leaders

  • Niels Riksen, MD, PhD, professor in vascular medicine
  • Mihai Netea, MD, PhD, professor in experimental internal medicine
  • Leo Joosten, PhD, professor in inflammatory disorders

 

Group members

  • Sam Keating, PhD, postdoctoral researcher
  • Siroon Bekkering, PhD, postdoctoral researcher
  • Charlotte van der Heijden, MD, PhD student
  • Marlies Noz, MD, PhD student
  • Anouk Janssen, MD, PhD student
  • Laszlo Groh, MSc, PhD student
  • Julia van Tuijl, MD, PhD student


Selected publications

  • Bekkering S*, Arts RJW*, Novakovic B, Kourtzelis I, Popa C, ter Horst R, van Tuijl J, Simon A, Stunnenberg H, Joosten LAB, Chavakis T, van der Meer JWM, Riksen NP*, Netea MG*. The mevalonate pathway drives metabolic and epigenetic reprogramming during induction of trained immunity. Cell. 2018, Jan 11
  • Arts RJ, Novakovic B, Ter Horst R, Carvalho A, Bekkering S, Lachmandas E, Rodrigues F, Silvestre R, Cheng SC, Wang SY, Habibi E, Goncalves LG, Mesquita I, Cunha C, van Laarhoven A, van de Veerdonk FL, Williams DL, van der Meer JW, Logie C, O'Neill LA, Dinarello CA, Riksen NP, van Crevel R, Clish C, Notebaart RA, Joosten LA, Stunnenberg HG, Xavier RJ, Netea MG. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 2016;24:807-819.
  • Christ A, Bekkering S, Latz E*, Riksen NP*. Long-term activation of the innate immune system in atherosclerosis. Sem Immunol. 2016;28(4):384-93.
  • Bekkering S, van den Munckhof I, Nielen T, Lamfers E, Dinarello C, Rutten J, de Graaf J, Joosten LA, Netea MG, Gomes ME, Riksen NP. Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo. Atherosclerosis. 2016;254:228-36.
  • van der Valk FM, Bekkering S, Kroon J, Yeang C, Van den Bossche J, van Buul JD, Ravandi A, Nederveen AJ, Verberne HJ, Scipione C, Nieuwdorp M, Joosten LA, Netea MG, Koschinsky ML, Witztum JL, Tsimikas S, Riksen NP, Stroes ES. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation. 2016;134(8):611-24.
  • Bekkering S, Quintin J, Joosten LA, van der Meer JW, 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. 2014;34:1731-8.
  • Bekkering S, Joosten LA, van der Meer JW, Netea MG, Riksen NP. Trained innate immunity and atherosclerosis. Curr Opin Lipidol. 2013;24(6):487-92. 

 

Financial support

  • Horizon 2020 grant REPROGRAM (H2020-PHC-2015-667873-2)
  • Netherlands Heart Foundation (2012T051 to NPR)
  • European Federation for the Study of Diabetes
  • Radboud University