Oligomeric S100A4 is associated with monocyte innate immune memory and bypass of tolerance to subsequent stimulation with lipopolysaccharides

Michel Neidhart; Agnieszka Pajak; Katerina Laskari; Niels P. Riksen; Leo A.B. Joosten; Mihai G. Netea; Esther Lutgens; Eric S.G. Stroes; Adrian Ciurea; Oliver Distler; Mariam Grigorian; Emmanuel Karouzakis

doi:10.3389/fimmu.2019.00791

Oligomeric S100A4 is associated with monocyte innate immune memory and bypass of tolerance to subsequent stimulation with lipopolysaccharides

Michel Neidhart^*, Agnieszka Pajak, Katerina Laskari, Niels P. Riksen, Leo A.B. Joosten, Mihai G. Netea, Esther Lutgens, Eric S.G. Stroes, Adrian Ciurea, Oliver Distler, Mariam Grigorian, Emmanuel Karouzakis

^*Corresponding author for this work

7 Citations (Scopus)

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Abstract

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.

Original language	English
Article number	791
Journal	Frontiers in Immunology
Volume	10
Number of pages	17
ISSN	1664-3224
DOIs	https://doi.org/10.3389/fimmu.2019.00791
Publication status	Published - 2019

Keywords

DAMPs
Epigenetic
Rheumatoid arthritis
S100A4 protein
Trained immunity

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10.3389/fimmu.2019.00791Licence: CC BY

Oligomeric S100A4 is associated with monocyte innate immune memory and bypass of tolerance to subsequent stimulation with lipopolysaccharidesFinal published version, 3.58 MBLicence: CC BY

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Neidhart, M., Pajak, A., Laskari, K., Riksen, N. P., Joosten, L. A. B., Netea, M. G., Lutgens, E., Stroes, E. S. G., Ciurea, A., Distler, O., Grigorian, M., & Karouzakis, E. (2019). Oligomeric S100A4 is associated with monocyte innate immune memory and bypass of tolerance to subsequent stimulation with lipopolysaccharides. Frontiers in Immunology, 10, [791]. https://doi.org/10.3389/fimmu.2019.00791

Neidhart, M, Pajak, A, Laskari, K, Riksen, NP, Joosten, LAB, Netea, MG, Lutgens, E, Stroes, ESG, Ciurea, A, Distler, O, Grigorian, M & Karouzakis, E 2019, 'Oligomeric S100A4 is associated with monocyte innate immune memory and bypass of tolerance to subsequent stimulation with lipopolysaccharides', Frontiers in Immunology, vol. 10, 791. https://doi.org/10.3389/fimmu.2019.00791

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title = "Oligomeric S100A4 is associated with monocyte innate immune memory and bypass of tolerance to subsequent stimulation with lipopolysaccharides",

abstract = "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.",

keywords = "DAMPs, Epigenetic, Rheumatoid arthritis, S100A4 protein, Trained immunity",

author = "Michel Neidhart and Agnieszka Pajak and Katerina Laskari and Riksen, {Niels P.} and Joosten, {Leo A.B.} and Netea, {Mihai G.} and Esther Lutgens and Stroes, {Eric S.G.} and Adrian Ciurea and Oliver Distler and Mariam Grigorian and Emmanuel Karouzakis",

year = "2019",

doi = "10.3389/fimmu.2019.00791",

language = "English",

volume = "10",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Research Foundation",

}

TY - JOUR

T1 - Oligomeric S100A4 is associated with monocyte innate immune memory and bypass of tolerance to subsequent stimulation with lipopolysaccharides

AU - Neidhart, Michel

AU - Pajak, Agnieszka

AU - Laskari, Katerina

AU - Riksen, Niels P.

AU - Joosten, Leo A.B.

AU - Netea, Mihai G.

AU - Lutgens, Esther

AU - Stroes, Eric S.G.

AU - Ciurea, Adrian

AU - Distler, Oliver

AU - Grigorian, Mariam

AU - Karouzakis, Emmanuel

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - DAMPs

KW - Epigenetic

KW - Rheumatoid arthritis

KW - S100A4 protein

KW - Trained immunity

U2 - 10.3389/fimmu.2019.00791

DO - 10.3389/fimmu.2019.00791

M3 - Journal article

C2 - 31037071

AN - SCOPUS:85065484540

SN - 1664-3224

VL - 10

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 791

ER -

Oligomeric S100A4 is associated with monocyte innate immune memory and bypass of tolerance to subsequent stimulation with lipopolysaccharides

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