Epigenetic reprograming
Rheumatoid arthritis (RA) involves multiple compartments and cellular systems, including lymphocyte subsets, activated monocytes / macrophages and aggressive synovial fibroblasts.
Our hypothesis is that chronicity is associated with cellular memory, leading to stably activated and/or hyperreactive cells. This involves epigenetic mechanisms in a defined genetic background. These cells communicate through an network of interactions, resulting at end in destruction of the joint. To cure the disease, it will be essential to disrupt the mechanisms leading to these activated phenotypes. In monocytes, this could be possible by interfering with epigenetic effector mechanisms, e.g. TET enzymes and DNA hydroxymethylation (which is a sign of gene activation), whereas in RA synovial fibroblasts, a possibly would be to reverse global DNA hypomethylation using methyl donors and inhibitors of the polyamine backconversion, a pathway regulated by permidine / spermine N1 acethyltransferase (SSAT1).
Current Projects
Citrullinated peptides triggering innate immune memory
In rheumatoid arthritis, citrullinated peptides are regarded as non-self neoepitopes in a given genetic background and lead to the production of anti-citrullinated peptides antibodies that are very specific for the disease. We showed that citrullinated vimentin (but not native vimentin) have a direct effect on the activity of monocytes. It induces a process of innate immune memory (also called trained immunity), which allows the cells to increase their response to subsequent unrelated stimuli. Using ATAQ-Seq, we found that citrullinated vimentin produces chromatin changes, allowing increased expression of genes encoding proteins involved in signalling pathways and inflammation. This process may contribute to a chronic inflammatory state. An aim of the project is to target the mechanisms leading to trained immunity that are triggered by citrullinated vimentin.
Coworkers
- Emmanuel Karouzakis (PhD)
- Shweta Sabu (MSc ETH pharmaceutical science)
Cooperations
- Niels P Riksen, Department of Internal Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 8, Nijmegen, The Netherlands.
- Mariam Grigorian, Faculty of Health Sciences, Center of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
- Neidhart M, Pajak A, Laskari K, Riksen NP, Joosten LAB, Netea MG, Lutgens E, Stroes ESG, Ciurea A, Distler O, Grigorian M, Karouzakis E.
Oligomeric S100A4 Is Associated With Monocyte Innate Immune Memory and Bypass of Tolerance to Subsequent Stimulation With Lipopolysaccharides.
Front Immunol. 2019 Apr 15;10:791. doi: 10.3389/fimmu.2019.00791. eCollection 2019.
- Sun F, Abreu-Rodriguez I, Ye S, Gay S, Distler O, Neidhart M, Karouzakis E.
TET1 is an important transcriptional activator of TNFα expression in macrophages.
PLoS One. 2019 Jun 19;14(6):e0218551. doi: 10.1371/journal.pone.0218551. - Hoogeveen RM, Nahrendorf M, Riksen NP, Netea MG, de Winther MPJ, Lutgens E, Nordestgaard BG, Neidhart M, Stroes ESG, Catapano AL, Bekkering S.
Monocyte and haematopoietic progenitor reprogramming as common mechanism underlying chronic inflammatory and cardiovascular diseases.
Eur Heart J. 2018 Oct 7;39(38):3521-3527. doi: 10.1093/eurheartj/ehx581.