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^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Systemische Entzündungsforschung

198 Zitate (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.

Originalsprache	Englisch
Zeitschrift	Immunity
Jahrgang	54
Ausgabenummer	5
Seiten (von - bis)	1002-1021.e10
ISSN	1074-7613
DOIs	https://doi.org/10.1016/j.immuni.2021.03.003
Publikationsstatus	Veröffentlicht - 11.05.2021

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This work was supported by the DFG ( FG 2886–TP04 to U.S., TP08 to D.M. and M.H.H., Z-project [A.K.]; CRC1181-B03 to M.H.H., A05 to S.F., and Z2 to T.B.; EXC2167 PMI, TI-3 to J.K.), the European Union (ERC Synergy grant 810316 4DnanoSCOPE to G.S.), the EU/EFPIA IMI 2 RTCure ( 77735 ). X.C. was supported by the Chinese Scholarship Council . We thank the Optical imaging center Erlangen and the Precinical imaging platform Erlangen. We further thank U. Appelt, M. Mroz, H. Danzer, D. Beckmann, K. von Dalwigk, A. Rauschenberg and L. Möller for technical assistance, F. Hartmann for collation of patient characteristics, and M. Göksu for recruitment of human synovial tissue. We also thank G. Kollias, BSRC Alexander Fleming, for sharing Col6a1-cre mice. The graphical abstract was created by Sundary Sormendi using Biorender.com . A.F. received institutional research funding from Pfizer, Roche, UCB, Nascient, Mestag, and GSK. The other authors declare no competing interests. This work was supported by the DFG (FG 2886?TP04 to U.S. TP08 to D.M. and M.H.H. Z-project [A.K.]; CRC1181-B03 to M.H.H. A05 to S.F. and Z2 to T.B.; EXC2167 PMI, TI-3 to J.K.), the European Union (ERC Synergy grant 810316 4DnanoSCOPE to G.S.), the EU/EFPIA IMI 2 RTCure (77735). X.C. was supported by the Chinese Scholarship Council. We thank the Optical imaging center Erlangen and the Precinical imaging platform Erlangen. We further thank U. Appelt, M. Mroz, H. Danzer, D. Beckmann, K. von Dalwigk, A. Rauschenberg and L. M?ller for technical assistance, F. Hartmann for collation of patient characteristics, and M. G?ksu for recruitment of human synovial tissue. We also thank G. Kollias, BSRC Alexander Fleming, for sharing Col6a1-cre mice. The graphical abstract was created by Sundary Sormendi using Biorender.com. Conceptualization, J.F. M.B. H.B. M.H. H.P.K. U.S. A.G. J.A. K.K. A.F. A.P.C. G.K. C.D.B. G.S. D.M. and M.H.H.; Methodology, J.F. C.R. M.B. B.W. H.B. K.I.W. T.M. O.A. F.T.A. A.K.-P. A.P.C. I.W. J.A. R.K. A.H. H.P.K. B.F. L.K. U.S. T.B. A.G. K.K. and M.H.H.; Software, O.A.; Formal analysis, M.B. J.T. H.Z. P.K. R.K. S.F. K.R. D.M. and M.H.H.; Investigation, J.F. C.R. M.B. B.W. H.B. S-J.P. D.W. A.F. S.F. F.T.A. M.E. Z.S. I.W. B.F. and L.K.; Resources, V.T. G.S. K.R. A.K. J.D. A.B.E. J.A. T.B. J.K. J.W. T.R.H. V.W. K.K. A.F. and C.D.B.; Data Curation, A.B.E. K.R.; Writing ? Original Draft, M.H.H.; Writing, Review & Editing, M.B. A.F. J.K. C.D.B. D.M. G.S. and M.H.H.; Visualization, J.F. C.R. M.B. J.T. S.F. H.B. T.M. A.G. and M.H.H.; Supervision and Project Administration, M.H.H.; Funding Acquisition, K.K. G.S. S.F. G.K. C.D.B. D.M. and M.H.H. A.F. received institutional research funding from Pfizer, Roche, UCB, Nascient, Mestag, and GSK. The other authors declare no competing interests. Mice on the BALB/c and C57BL/6 backgrounds and Wistar rats were bred in house and kept in temperature- and humidity-controlled facilities at the University of Erlangen, Germany, the Medical University of Vienna, Austria, or the Faculty of Medicine, University of Belgrade, Serbia, respectively, group housed with free access to food and water and 12 h light/dark cycles. Complement C3-deficient C3 tm1Crr mice were bought from Jackson, SCID mice (CB17/Icr-Prkdc scid ) and NOD/ShiLtJ were from Charles River Germany. C3ar −/− mice were from Jörg Köhl, University of Lübeck, Germany. Rag1 −/− mice and Col6a1 cre :R26-tdTomato reporter mice, both on C57BL/6 background, were gifts from Mario Zaiss and Clemens Neufert, respectively, both from the University of Erlangen. The inducible hTNFtg mice homozygous for the Tg_rtTA2S transgene and the human TNFα transgenes have been described previously ( Retser et al., 2013 ). Mice expressing a Cre recombinase under the Cx3cr1 promoter together with a Cre-inducible diphtheria toxin (DT) receptor (Cx3cr1cre;iDTR mice) were generated by breeding C57BL/6-Gt(ROSA)26Sortm1(HBEGF)Awai/J (iDTR) purchased from Jackson with STOCK Tg(Cx3cr1cre)MW126Gsat/Mmucd mice (Cx3cr1cre) (identification number 036395-UCD) from the Mutant Mouse Regional Resource Center (MMRC), a National Institutes of Health (NIH)- funded strain repository. Resident tissue macrophages become specifically depleted in DT-treated Cx3cr1cre:iDTR mice several days after DT injection, since blood monocytes repopulate within 48 h after DT application. Wistar rats were derived from Charles River. The animal studies were approved by the local ethical committees and conducted according to the guidelines of the Federation of European Laboratory Animal Science Associations (FELASA). Healthy adult animals 8-12 weeks old, both male and female were used in studies. All experiments were performed using age- and sex-matched littermate controls. If possible, mice were allocated randomly into groups by a computer-based random number generator ( http://www.randomizer.org ), so that each cage contained animals of every group to compensate for possible cage effects. Power analysis was performed before begin of the experiments on the basis of effect size estimates from previous experience.

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SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

Dokumente

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",

publisher = "Cell Press",

number = "5",

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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, Jg. 54, Nr. 5, S. 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 - https://www.scopus.com/pages/publications/85103957657

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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