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.

Objectives

In the current proposal, we aim to better investigate pathogen-associated and damage-associated molecular pattern (PAMP and DAMP, respectively)-induced trained immunity in healthy individuals and RA patients. The association of epigenetic modifications with transcriptomic data will identify gene promoters, enhancers and transcription factor motifs possibly involved in trained immunity. Gene silencing will give more insights into their function. By targeting specific mechanisms of trained immunity on either molecular, protein or epigenetic level, novel therapeutic approaches could be developed.

Patient Voice

For this laboratory project, based on novel technologies, patients have not been directly involved
in the design of the experiments. However, the development of novel potential therapeutic targets and strategies will clearly benefit the patients.

Interim results

Peripheral blood monocytes (PBMCs) of healthy volunteers exposed to oligomeric S100A4 (oS100A4) showed increased IL-1β, IL-6, and TNFα in response to the liposaccharide of Escherichia coli (LPS E.coli). RNASEq upon β-glucan or oS100A4 revealed similar changes in chemokines/cytokines and epigenetic effectors; 17 epigenetic effectors correlated with chemokine/cytokine gene expression; PRDM8 was associated with more chemokine and cytokine transcripts. Knockdown of PRDM8 abolished trained immunity induced by oS100A4. In RA, plasma S100A4 correlated with increased CSF2, and increased PRDM8 transcription in PBMCs was associated with increased plasma CCL5 and IL-6, as well as therapy resistance.

 

In addition, citrullinated vimentin and the lipopolysaccharide of Porphyromonas gingivalis (LPS P.gingivalis) induced training in most healthy controls, as suggested by the significantly increased levels of secreted interleukin-6 (IL-6), the chemokine CXCL-1, and the Macrophage Inflammatory Protein 3a. The native vimentin had significantly less training capacities compared to the citrullinated one. In RA, while the levels of released IL-6 were similar to controls after stimulation with LPS E.coli, we observed a significantly increased immune response after stimulation with LPS P. gingivalis, citrullinated vimentin or oS100A4.

Conclusions

Citrullinated vimentin, LPS of P.gingivalis and oS100Α4 can induce trained immunity in vitro. RA monocytes respond stronger than healthy controls to PAMPs/DAMPS. These observations point towards a possible failed resolution of inflammation in RA due to training capacities of the innate immune cells.

Publications

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;10:791.

Facts and figures

Project lead
K Laskari
Athens University Medical School
katerina_laskari@yahoo.gr
FOREUM research grant: €50'000
Project Duration: 2019–2020

Meet the team

K Laskari
Athens University Medical School
P Sfikakis
Athens University Medical School
Prof. Dr. O Distler
University of Zurich