The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts

Jasna Friščić; Martin Böttcher; Christiane Reinwald; Heiko Bruns; Benjamin Wirth; Samantha Josefine Popp; Kellie Irene Walker; Jochen A. Ackermann; Xi Chen; Jason Turner; Honglin Zhu; Lisa Seyler; Maximilien Euler; Philipp Kirchner; René Krüger; Arif B. Ekici; Triin Major; Oliver Aust; Daniela Weidner; Anita Fischer; Fabian T. Andes; Zeljka Stanojevic; Vladimir Trajkovic; Martin Herrmann; Adelheid Korb-Pap; Isabel Wank; Andreas Hess; Johnathan Winter; Viktor Wixler; Jörg Distler; Günter Steiner; Hans P. Kiener; Benjamin Frey; Lasse Kling; Karim Raza; Silke Frey; Arnd Kleyer; Tobias Bäuerle; Timothy R. Hughes; Anika Grüneboom; Ulrike Steffen; Gerhard Krönke; Adam P. Croft; Andrew Filer; Jörg Köhl; Kerstin Klein; Christopher D. Buckley; Georg Schett; Dimitrios Mougiakakos; Markus H. Hoffmann

doi:10.1016/j.immuni.2021.03.003

The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts

Jasna Friščić, Martin Böttcher, Christiane Reinwald, Heiko Bruns, Benjamin Wirth, Samantha Josefine Popp, Kellie Irene Walker, Jochen A. Ackermann, Xi Chen, Jason Turner, Honglin Zhu, Lisa Seyler, Maximilien Euler, Philipp Kirchner, René Krüger, Arif B. Ekici, Triin Major, Oliver Aust, Daniela Weidner, Anita FischerFabian T. Andes, Zeljka Stanojevic, Vladimir Trajkovic, Martin Herrmann, Adelheid Korb-Pap, Isabel Wank, Andreas Hess, Johnathan Winter, Viktor Wixler, Jörg Distler, Günter Steiner, Hans P. Kiener, Benjamin Frey, Lasse Kling, Karim Raza, Silke Frey, Arnd Kleyer, Tobias Bäuerle, Timothy R. Hughes, Anika Grüneboom, Ulrike Steffen, Gerhard Krönke, Adam P. Croft, Andrew Filer, Jörg Köhl, Kerstin Klein, Christopher D. Buckley, Georg Schett, Dimitrios Mougiakakos, Markus H. Hoffmann^*

^*Corresponding author for this work

Institute of Systemic Inflamation Research

5 Citations (Scopus)

Abstract

Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.

Original language	English
Journal	Immunity
Volume	54
Issue number	5
Pages (from-to)	1002-1021.e10
ISSN	1074-7613
DOIs	https://doi.org/10.1016/j.immuni.2021.03.003
Publication status	Published - 11.05.2021

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Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2021.03.003

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Friščić, J., Böttcher, M., Reinwald, C., Bruns, H., Wirth, B., Popp, S. J., Walker, K. I., Ackermann, J. A., Chen, X., Turner, J., Zhu, H., Seyler, L., Euler, M., Kirchner, P., Krüger, R., Ekici, A. B., Major, T., Aust, O., Weidner, D., ... Hoffmann, M. H. (2021). The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts. Immunity, 54(5), 1002-1021.e10. https://doi.org/10.1016/j.immuni.2021.03.003

@article{e831cfd1ecf74f8a81082efa3e120826,

title = "The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts",

abstract = "Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.",

author = "Jasna Fri{\v s}{\v c}i{\'c} and Martin B{\"o}ttcher and Christiane Reinwald and Heiko Bruns and Benjamin Wirth and Popp, {Samantha Josefine} and Walker, {Kellie Irene} and Ackermann, {Jochen A.} and Xi Chen and Jason Turner and Honglin Zhu and Lisa Seyler and Maximilien Euler and Philipp Kirchner and Ren{\'e} Kr{\"u}ger and Ekici, {Arif B.} and Triin Major and Oliver Aust and Daniela Weidner and Anita Fischer and Andes, {Fabian T.} and Zeljka Stanojevic and Vladimir Trajkovic and Martin Herrmann and Adelheid Korb-Pap and Isabel Wank and Andreas Hess and Johnathan Winter and Viktor Wixler and J{\"o}rg Distler and G{\"u}nter Steiner and Kiener, {Hans P.} and Benjamin Frey and Lasse Kling and Karim Raza and Silke Frey and Arnd Kleyer and Tobias B{\"a}uerle and Hughes, {Timothy R.} and Anika Gr{\"u}neboom and Ulrike Steffen and Gerhard Kr{\"o}nke and Croft, {Adam P.} and Andrew Filer and J{\"o}rg K{\"o}hl and Kerstin Klein and Buckley, {Christopher D.} and Georg Schett and Dimitrios Mougiakakos and Hoffmann, {Markus H.}",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = may,

day = "11",

doi = "10.1016/j.immuni.2021.03.003",

language = "English",

volume = "54",

pages = "1002--1021.e10",

journal = "Immunity",

issn = "1074-7613",

number = "5",

}

Friščić, J, Böttcher, M, Reinwald, C, Bruns, H, Wirth, B, Popp, SJ, Walker, KI, Ackermann, JA, Chen, X, Turner, J, Zhu, H, Seyler, L, Euler, M, Kirchner, P, Krüger, R, Ekici, AB, Major, T, Aust, O, Weidner, D, Fischer, A, Andes, FT, Stanojevic, Z, Trajkovic, V, Herrmann, M, Korb-Pap, A, Wank, I, Hess, A, Winter, J, Wixler, V, Distler, J, Steiner, G, Kiener, HP, Frey, B, Kling, L, Raza, K, Frey, S, Kleyer, A, Bäuerle, T, Hughes, TR, Grüneboom, A, Steffen, U, Krönke, G, Croft, AP, Filer, A, Köhl, J, Klein, K, Buckley, CD, Schett, G, Mougiakakos, D & Hoffmann, MH 2021, 'The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts', Immunity, vol. 54, no. 5, pp. 1002-1021.e10. https://doi.org/10.1016/j.immuni.2021.03.003

TY - JOUR

T1 - The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts

AU - Friščić, Jasna

AU - Böttcher, Martin

AU - Reinwald, Christiane

AU - Bruns, Heiko

AU - Wirth, Benjamin

AU - Popp, Samantha Josefine

AU - Walker, Kellie Irene

AU - Ackermann, Jochen A.

AU - Chen, Xi

AU - Turner, Jason

AU - Zhu, Honglin

AU - Seyler, Lisa

AU - Euler, Maximilien

AU - Kirchner, Philipp

AU - Krüger, René

AU - Ekici, Arif B.

AU - Major, Triin

AU - Aust, Oliver

AU - Weidner, Daniela

AU - Fischer, Anita

AU - Andes, Fabian T.

AU - Stanojevic, Zeljka

AU - Trajkovic, Vladimir

AU - Herrmann, Martin

AU - Korb-Pap, Adelheid

AU - Wank, Isabel

AU - Hess, Andreas

AU - Winter, Johnathan

AU - Wixler, Viktor

AU - Distler, Jörg

AU - Steiner, Günter

AU - Kiener, Hans P.

AU - Frey, Benjamin

AU - Kling, Lasse

AU - Raza, Karim

AU - Frey, Silke

AU - Kleyer, Arnd

AU - Bäuerle, Tobias

AU - Hughes, Timothy R.

AU - Grüneboom, Anika

AU - Steffen, Ulrike

AU - Krönke, Gerhard

AU - Croft, Adam P.

AU - Filer, Andrew

AU - Köhl, Jörg

AU - Klein, Kerstin

AU - Buckley, Christopher D.

AU - Schett, Georg

AU - Mougiakakos, Dimitrios

AU - Hoffmann, Markus H.

PY - 2021/5/11

Y1 - 2021/5/11

N2 - Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.

AB - Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.

UR - http://www.scopus.com/inward/record.url?scp=85103957657&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2021.03.003

DO - 10.1016/j.immuni.2021.03.003

M3 - Journal articles

C2 - 33761330

AN - SCOPUS:85103957657

SN - 1074-7613

VL - 54

SP - 1002-1021.e10

JO - Immunity

JF - Immunity

IS - 5

ER -

The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts

Abstract

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