Trained immunity and auto-inflammatory diseases
Radboud university medical center, Nijmegen, the Netherlands
In addition to several microbial ligands, endogenous danger signals such oxidized lipids, glycosylated proteins or uric acid can induce a state of trained immunity (TRIM) in myeloid cells. All these endogenous triggers have been linked to the pathogenesis of several auto-inflammatory disease, including type 2 diabetes, atherosclerosis and gout. Moreover, these chronic inflammatory disorders have a common hallmark: continuous activation of the innate immune system.
Gout is the most frequent rheumatic disorder and hyperuricemia is seen as the main culprit for the development of gout. Reducing serum uric acid concentrations in combination with an anti-inflammatory therapy is nowadays the standard therapy for gout patients. Local long-lasting activation of the innate immune cells (monocytes or macrophages) by endogenous triggers, e.g. uric acid, in combination with a second event may lead to flares of gouty arthritis. We envision that the enhanced inflammatory status of uric acid trained monocytes or macrophages leads to chronic inflammation.
The aim of our group is to explore the mechanisms of uric acid-induced TRIM in hyperuricemia associated inflammatory diseases with the main focus on gout. We will work towards the identification of epigenetic and immunometabolic programs which are causative for the induction of uric acid-induced trained immunity. In addition, we aim to understand why certain individuals with hyperuricemia do not develop a state of TRIM in myeloid cells. In large cohorts of gout patients we perform confirmational studies to validate the identified pathways, specific targets and potential inhibitors of uric acid-induced TRIM.
- Leo Joosten, PhD, professor in inflammatory disorders
- Mihai Netea, MD, PhD, professor in experimental internal medicine
- Niels Riksen, MD, PhD, professor in vascular medicine
- Tania Crisan, MD, PhD student
- Maartje Cleophas, PhD student
- Viola Kluck, MD, PhD student
- Rob ter Horst, PhD student
- Rosanne van Deuren, PhD student
- Sam Keating, Postdoc researcher
- Alex Hoischen, PhD, Associate professor Immunogenetics
- Anette Christ, Patrick Günther, Mario A.R. Lauterbach, Peter Duewell, Debjani Biswas, Karin Pelka, Claus J. Scholz, Marije Oosting, Kristian Haendler, Kevin Baßler, Kathrin Klee, Jonas Schulte-Schrepping, Thomas Ulas, Simone J.C.F.M. Moorlag, Vinod Kumar, Min Hi Park, Leo A.B. Joosten, Laszlo A. Groh, Niels P. Riksen, Terje Espevik, Andreas Schlitzer, Yang Li, Michael L. Fitzgerald, Mihai G. Netea, Joachim L. Schultze and Eicke Latz Western diet triggers NLRP3-dependent innate immune reprograming. Cell. 2018, Jan 11
- 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
- Crişan TO, Cleophas MCP, Novakovic B, Erler K, van de Veerdonk FL, Stunnenberg HG, Netea MG, Dinarello CA, Joosten LAB. Uric acid priming in human monocytes is driven by the AKT-PRAS40 autophagy pathway. Proc Natl Acad Sci U S A. 2017;114(21):5485-5490.
- Spaetgens B, de Vries F, Driessen JHM, Leufkens HG, Souverein PC, Boonen A, van der Meer JWM, Joosten LAB. Risk of infections in patients with gout: a population-based cohort study. Sci Rep. 2017;7(1):1429.
- Cleophas MC, Crişan TO, Joosten LAB. Factors modulating the inflammatory response in acute gouty arthritis. Curr Opin Rheumatol. 2017;29(2):163-170.
- Nakayama A, et al., Eurogout Consortium. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis. 2017;76(5):869-877.
- Crișan TO, Cleophas MC, Oosting M, Lemmers H, Toenhake-Dijkstra H, Netea MG, Jansen TL, Joosten LAB. Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Ann Rheum Dis. 2016;75(4):755-62
- Cleophas MC, Crişan TO, Lemmers H, Toenhake-Dijkstra H, Fossati G, Jansen TL, Dinarello CA, Netea MG, Joosten LAB. Suppression of monosodium urate crystal-induced cytokine production by butyrate is mediated by the inhibition of class I histone deacetylases. Ann Rheum Dis. 2016;75(3):593-600.
- Netea MG, Joosten LAB, Latz E, Mills KH, Natoli G, Stunnenberg HG, O'Neill LA, Xavier RJ. Trained immunity: A program of innate immune memory in health and disease. Science. 2016;352(6284):aaf1098.
- Bekkering S, Joosten LAB, van der Meer JW, Netea MG, Riksen NP. Trained innate immunity and atherosclerosis. Curr Opin Lipidol. 2013;24(6):487-92.
- Christ A, Bekkering S, Latz E, Riksen NP. Long-term activation of the innate immune system in atherosclerosis. Semin Immunol 2016; 28:384-93.
- Mylona EE, Mouktaroudi M, Crisan TO, Makri S, Pistiki A, Georgitsi M, Savva A, Netea MG, van der Meer JW, Giamarellos-Bourboulis EJ, Joosten LAB. Enhanced interleukin-1β production of PBMCs from patients with gout after stimulation with Toll-like receptor-2 ligands and urate crystals. Arthritis Res Ther. 2012;14(4):R158
- Dutch Arthritis Foundation (NR-12-2-303)
- Horizon 2020 grant REPROGRAM (H2020-PHC-2015-667873-2)
- Competitiveness Operational Program Grant of the Romanian Ministry of European Funds (HINT, ID P_37_762; MySMIS 103587)
- Radboud University Medical Centre grant (2017)