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Front Immunol. 2019 Apr 15;10:791. doi: 10.3389/fimmu.2019.00791. eCollection 2019.

Oligomeric S100A4 Is Associated With Monocyte Innate Immune Memory and Bypass of Tolerance to Subsequent Stimulation With Lipopolysaccharides.

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Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands.
Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania.
Department for Immunology & Metabolism, Life and Medical Science Institute (LIMES), University of Bonn, Bonn, Germany.
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany.
Department of Medical Biochemistry, Amsterdam University Medical Centre, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, Netherlands.
Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
Faculty of Health Sciences, Center of Neuroscience, University of Copenhagen, Copenhagen, Denmark.


Objectives: Most DAMPs in inflammatory diseases are TLR2- and TLR4-ligands and according to the current concept, repeated stimuli would result in tolerance. Aims of the study were to verify this assumption, to investigate whether epigenetic effectors are involved and to explore the situation in rheumatoid arthritis (RA). Methods: A trained immunity (TI) and tolerance protocol was established using peripheral blood monocytes from healthy donors, β-glucan and lipopolysaccharide (LPS). The training or tolerance capacities of RA-relevant DAMPs were tested. Results: β-Glucan-, oS100A4-, HMBG1-, and HSP90-pretreated monocytes showed increased IL-6 responses to LPS re-stimulation. β-Glucan, oS100A and tenascin C induced training of monocytes to release more TNFα. In comparison to β-glucan, most DAMPs tested induced less TI, with exception of oS100A4. Monocytes exposed to oS100A4 showed increased IL-1β, IL-6, and TNFα in response to LPS, in spite that both stimulate TLR4. 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 TI induced by oS100A4. In RA, plasma S100A4 correlated with increased CSF2, and increased PRDM8 transcription in RA monocytes was associated with increased plasma CCL5 and IL-6, as well as therapy-resistance. Conclusion: Bypass of tolerance by DAMPs might be a phenomenon as important as TI, since it could explain how chronic inflammation can be maintained in spite of an environment with multiple TLR2/TLR4-ligands. In RA monocytes, a PRDM8-dependent TI mechanism could be responsible for sustained chemokine/cytokines levels.


DAMPs; S100A4 protein; epigenetic; rheumatoid arthritis; trained immunity

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