Customary understanding of innate immunity functioning assumes its inferiority to adaptive immunity due to its primitive character, non-specific mode of action and inability to mount immunological memory. However, this dogma has been recently questioned. Monocytes pretreated with heat-inactivated Candida albicans or its the most potent component, b-glucan, increases production of TNFa and IL-6 upon restimulation with different non-related microbial stimuli or Mycobacteria tuberculosis. This new kind of immunological memory has been termed "Trained Immunity" (TI). We hypothesize that during the course of RA early events might influence the macrophages to react more severely to specific stimuli later. It is reasonable to think that first occurrence of danger signals within the joint cavity (including citrulllinated proteins) or in the blood circulation could predispose either circulating or joint residing monocytes / macrophages for augmented response upon secondary encounter with another signal. Subsequently, activated macrophages by its secretory activity would induce further inflammatory responses and drive more aggressive phenotypes of synovial fibroblasts. Particularly, we test the training properties of multimeric S100A4 and oxidative LDL on macrophages, at the levels of gene expression, epigenetic mechanisms and changed metabolism. This project might provide information about the activation of monocytes in RA, possible epigenetic targets and comorbidities with cardiovascular diseases.
Prof. Leo A.B. Joosten, Faculty of Medical Sciences, Radboud University, Nijmegen; Prof. Mariam Grigorian, Dept. of Neuroscience and Pharmacology, Faculty of Health and Medical Science, University of Copenhagen; Prof. Alberico L. Catapano, Alberico L. Catapano, Department of Pharmacological and Biomolecular Sciences, University of Milan.
EU Horizon 2020 Reprogram.
- Cerezo LA, Remáková M, Tomčik M, Gay S, Neidhart M, Lukanidin E, Pavelka K, Grigorian M, Vencovský J, Šenolt L. The metastasis-associated protein S100A4 promotes the inflammatory response of mononuclear cells via the TLR4 signalling pathway in rheumatoid arthritis. Rheumatology (Oxford). 2014 Aug;53(8):1520-6.
- Yonekawa K, Neidhart M, Altwegg LA, Wyss CA, Corti R, Vogl T, Grigorian M, Gay S, Lüscher TF, Maier W. Myeloid related proteins activate Toll-like receptor 4 in human acute coronary syndromes. Atherosclerosis. 2011 Oct;218(2):486-92. doi: 10.1016/j.atherosclerosis.2011.06.020. Epub 2011 Jun 17.
- Cerezo LA, Kuncová K, Mann H, Tomcík M, Zámecník J, Lukanidin E, Neidhart M, Gay S, Grigorian M, Vencovsky J, Senolt L. The metastasis promoting protein S100A4 is increased in idiopathic inflammatory myopathies. Rheumatology (Oxford). 2011 Oct;50(10):1766-72