Epigenetic regulation by DAMPs underlying trained immunity in health and disease
Concept
Trained immunity is a process of innate immune memory in which a primary stimulus, such as β-glucan, enhances the response of monocytes upon nonspecific re-stimulation. During trained immunity, an epigenetic reprogramming of monocytes is observed, characterized by histone methylation marks in pro-inflammatory genes and an increased production of TNFa and IL-6. In humans, apart from the protection from re-infection, this process might lead in the long-term to the development and/or persistence of chronic inflammatory conditions. The hypothesis that trained immunity contributes to the initiation and perpetuation of the inflammatory response in rheumatoid arthritis (RA) has not been investigated so far.
Facts and Figures
K Laskari
Athens University Medical School
katerina_laskari@yahoo.gr
Meet the Team
Athens University Medical School
University of Zurich
Final Results
Citrullinated vimentin, which functions as damage-associated pattern in rheumatoid arthritis, seems to induce trained immunity in vitro in healthy individuals, thereby promoting chronic inflammation. The monocytes undergo epigenetic modifications and metabolic changes, resulting in functional reprogramming and enhanced release of cytokines and chemokines upon restimulation. The differentiation to an invasive macrophage with proinflammatory signature turns the monocytes to a decisive player in the pathogenesis of rheumatoid arthritis. By targeting the specific mechanisms of trained immunity on either molecular, protein or epigenetic level, novel therapeutic approaches could be developed.
Lay Summary
The ability of monocytes to develop adaptive features and provide long-term protection against pathogenic reinfection is termed “trained immunity”. The cells undergo a transcriptional, metabolic and functional reprogramming toward a pre-activated state. Since citrullinated vimentin plays an important role in the pathogenesis of rheumatoid arthritis, we hypothesized that it functions as damage associated pattern and induces innate immune memory, thereby promoting chronic inflammation. We showed that citrullinated vimentin induces epigenetic modifications and metabolic changes in monocytes, probably through a STING and TBK1-dependent pathway, resulting in functional reprogramming and enhanced release of cytokines and chemokines upon restimulation. Our data suggest that citrullinated vimentin induces the differentiation to an invasive macrophage with proinflammatory signature that constitutes a decisive player in the pathogenesis of rheumatoid arthritis. By targeting the specific mechanisms of trained immunity on either molecular, protein or epigenetic level, novel therapeutic approaches could be developed.
Publications
- POS0368: itrullination induces epigenetic memory of the innate immune system. Laskari K, Sabu S, Distler O, Karouzakis E, Neidhart M. Annals of the Rheumatic Diseases 2021;80: 414. DOI: 10.1136/annrheumdis-2021-eular.3302
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