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

Jasna Friščić; Martin Böttcher; Christiane Reinwald; Heiko Bruns; Benjamin Writh; 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 Hermann; Adelheid Korb-Pap; Isabel Wank; Andreas Hess; Jonathan Winter; Viktor Wixler; Jörg Distler; Günter Steiner; Hans P. Kiener; Benjamin Frey; Lasse Kling; Karim Raza; Silke Frey; Arnd Kleyer; Tobias Bäuerle; Anika Grüneboom; Ulrike Steffen; Gerhard Krönke; Adam Croft; Andrew Filer; Jörg Köhl; Kerstin Klein; Christopher D. Buckley; Georg Schett; Dimitrious Mougiakakos; Markus H. Hoffmann

doi:10.1016/j.immuni.2021.03.003

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

Jasna Friščić, Martin Böttcher, Christiane Reinwald, Heiko Bruns, Benjamin Writh, 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 Hermann, Adelheid Korb-Pap, Isabel Wank, Andreas Hess, Jonathan Winter, Viktor Wixler, Jörg Distler, Günter Steiner, Hans P. Kiener, Benjamin Frey, Lasse Kling, Karim Raza, Silke Frey, Arnd Kleyer, Tobias Bäuerle, Anika Grüneboom, Ulrike Steffen, Gerhard Krönke, Adam Croft, Andrew Filer, Jörg Köhl, Kerstin Klein, Christopher D. Buckley, Georg Schett, Dimitrious Mougiakakos, Markus H. Hoffmann

Inflammation and Ageing

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Abstract

Here, we define the molecular and cellular mechanism of inflammation-mediated tissue priming that determines recurrence of arthritis at specific predilection sites. Re-exposure of joints to inflammatory stimuli caused prolonged and aggravated clinical signs of experimental arthritis as well as higher levels of inflammation and tissue damage. Tissue priming developed locally and was independent of the adaptive immune system, but progressively spread to contralateral joints. Fibroblasts isolated from paws repeatedly exposed to inflammatory stimuli (“primed fibroblasts”) exhibited enhanced metabolic activity and NLRP3 inflammasome activation leading to functional changes with higher migration, invasiveness and osteoclastogenic potential. Human fibroblasts derived from established arthritis exhibited a similar primed functional phenotype as compared to fibroblasts from very early arthritis or non-inflamed joints. Transcriptomic and epigenomic analyses revealed upregulation of the complement system and confirmed metabolic reprogramming in primed fibroblasts. Genetic and pharmacological targeting of members of a complement C3 – C3a receptor – mTOR/HIF1α – NLRP3 axis reversed the primed fibroblast phenotype, induced a pro-resolving senescet phenotype and abrogated inflammatory tissue priming in vitro and in vivo. Our results suggest that inflammatory tissue priming is a process that leads to intracellular complement C3/C3aR activation and mTOR/HIF-1αmediated metabolic activation of fibroblasts that trigger enhanced NLRP3 inflammasome activity and in consequence facilitate recurrence of inflammation.

Original language	English
Pages (from-to)	1-31
Journal	Immunity
Volume	2021
Issue number	00
Early online date	23 Mar 2021
DOIs	https://doi.org/10.1016/j.immuni.2021.03.003
Publication status	E-pub ahead of print - 23 Mar 2021

Bibliographical note

Acknowledgements: 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.

Keywords

arthritis
cell metabolism
cellular senescence
complement system
inflammasome
inflammation
mechanistic target of rapamycin
synovial fibroblasts
tissue priming
trained immunity

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Friščić, J., Böttcher, M., Reinwald, C., Bruns, H., Writh, 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 articular fibroblasts. Immunity, 2021(00), 1-31. Advance online publication. https://doi.org/10.1016/j.immuni.2021.03.003

@article{411528b74fde4abbbc30eef3988bd6f2,

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

abstract = "Here, we define the molecular and cellular mechanism of inflammation-mediated tissue priming that determines recurrence of arthritis at specific predilection sites. Re-exposure of joints to inflammatory stimuli caused prolonged and aggravated clinical signs of experimental arthritis as well as higher levels of inflammation and tissue damage. Tissue priming developed locally and was independent of the adaptive immune system, but progressively spread to contralateral joints. Fibroblasts isolated from paws repeatedly exposed to inflammatory stimuli (“primed fibroblasts”) exhibited enhanced metabolic activity and NLRP3 inflammasome activation leading to functional changes with higher migration, invasiveness and osteoclastogenic potential. Human fibroblasts derived from established arthritis exhibited a similar primed functional phenotype as compared to fibroblasts from very early arthritis or non-inflamed joints. Transcriptomic and epigenomic analyses revealed upregulation of the complement system and confirmed metabolic reprogramming in primed fibroblasts. Genetic and pharmacological targeting of members of a complement C3 – C3a receptor – mTOR/HIF1α – NLRP3 axis reversed the primed fibroblast phenotype, induced a pro-resolving senescet phenotype and abrogated inflammatory tissue priming in vitro and in vivo. Our results suggest that inflammatory tissue priming is a process that leads to intracellular complement C3/C3aR activation and mTOR/HIF-1αmediated metabolic activation of fibroblasts that trigger enhanced NLRP3 inflammasome activity and in consequence facilitate recurrence of inflammation.",

keywords = "arthritis, cell metabolism, cellular senescence, complement system, inflammasome, inflammation, mechanistic target of rapamycin, synovial fibroblasts, tissue priming, trained immunity",

author = "Jasna Fri{\v s}{\v c}i{\'c} and Martin B{\"o}ttcher and Christiane Reinwald and Heiko Bruns and Benjamin Writh and Samantha-Josefine Popp 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 Hermann and Adelheid Korb-Pap and Isabel Wank and Andreas Hess and Jonathan 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 Anika Gr{\"u}neboom and Ulrike Steffen and Gerhard Kr{\"o}nke and Adam Croft and Andrew Filer and J{\"o}rg K{\"o}hl and Kerstin Klein and Buckley, {Christopher D.} and Georg Schett and Dimitrious Mougiakakos and Hoffmann, {Markus H.}",

note = "Acknowledgements: 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{\"o}ller for technical assistance, F. Hartmann for collation of patient characteristics, and M. G{\"o}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.",

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month = mar,

day = "23",

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

language = "English",

volume = "2021",

pages = "1--31",

journal = "Immunity",

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Friščić, J, Böttcher, M, Reinwald, C, Bruns, H, Writh, B, Popp, S-J, 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, Hermann, 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, Grüneboom, A, Steffen, U, Krönke, G, Croft, A , 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 articular fibroblasts', Immunity, vol. 2021, no. 00, pp. 1-31. 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 articular fibroblasts

AU - Friščić, Jasna

AU - Böttcher, Martin

AU - Reinwald, Christiane

AU - Bruns, Heiko

AU - Writh, 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 - Hermann, Martin

AU - Korb-Pap, Adelheid

AU - Wank, Isabel

AU - Hess, Andreas

AU - Winter, Jonathan

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 - Grüneboom, Anika

AU - Steffen, Ulrike

AU - Krönke, Gerhard

AU - Croft, Adam

AU - Filer, Andrew

AU - Köhl, Jörg

AU - Klein, Kerstin

AU - Buckley, Christopher D.

AU - Schett, Georg

AU - Mougiakakos, Dimitrious

AU - Hoffmann, Markus H.

N1 - Acknowledgements: 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.

PY - 2021/3/23

Y1 - 2021/3/23

N2 - Here, we define the molecular and cellular mechanism of inflammation-mediated tissue priming that determines recurrence of arthritis at specific predilection sites. Re-exposure of joints to inflammatory stimuli caused prolonged and aggravated clinical signs of experimental arthritis as well as higher levels of inflammation and tissue damage. Tissue priming developed locally and was independent of the adaptive immune system, but progressively spread to contralateral joints. Fibroblasts isolated from paws repeatedly exposed to inflammatory stimuli (“primed fibroblasts”) exhibited enhanced metabolic activity and NLRP3 inflammasome activation leading to functional changes with higher migration, invasiveness and osteoclastogenic potential. Human fibroblasts derived from established arthritis exhibited a similar primed functional phenotype as compared to fibroblasts from very early arthritis or non-inflamed joints. Transcriptomic and epigenomic analyses revealed upregulation of the complement system and confirmed metabolic reprogramming in primed fibroblasts. Genetic and pharmacological targeting of members of a complement C3 – C3a receptor – mTOR/HIF1α – NLRP3 axis reversed the primed fibroblast phenotype, induced a pro-resolving senescet phenotype and abrogated inflammatory tissue priming in vitro and in vivo. Our results suggest that inflammatory tissue priming is a process that leads to intracellular complement C3/C3aR activation and mTOR/HIF-1αmediated metabolic activation of fibroblasts that trigger enhanced NLRP3 inflammasome activity and in consequence facilitate recurrence of inflammation.

AB - Here, we define the molecular and cellular mechanism of inflammation-mediated tissue priming that determines recurrence of arthritis at specific predilection sites. Re-exposure of joints to inflammatory stimuli caused prolonged and aggravated clinical signs of experimental arthritis as well as higher levels of inflammation and tissue damage. Tissue priming developed locally and was independent of the adaptive immune system, but progressively spread to contralateral joints. Fibroblasts isolated from paws repeatedly exposed to inflammatory stimuli (“primed fibroblasts”) exhibited enhanced metabolic activity and NLRP3 inflammasome activation leading to functional changes with higher migration, invasiveness and osteoclastogenic potential. Human fibroblasts derived from established arthritis exhibited a similar primed functional phenotype as compared to fibroblasts from very early arthritis or non-inflamed joints. Transcriptomic and epigenomic analyses revealed upregulation of the complement system and confirmed metabolic reprogramming in primed fibroblasts. Genetic and pharmacological targeting of members of a complement C3 – C3a receptor – mTOR/HIF1α – NLRP3 axis reversed the primed fibroblast phenotype, induced a pro-resolving senescet phenotype and abrogated inflammatory tissue priming in vitro and in vivo. Our results suggest that inflammatory tissue priming is a process that leads to intracellular complement C3/C3aR activation and mTOR/HIF-1αmediated metabolic activation of fibroblasts that trigger enhanced NLRP3 inflammasome activity and in consequence facilitate recurrence of inflammation.

KW - arthritis

KW - cell metabolism

KW - cellular senescence

KW - complement system

KW - inflammasome

KW - inflammation

KW - mechanistic target of rapamycin

KW - synovial fibroblasts

KW - tissue priming

KW - trained immunity

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 - Article

SN - 1074-7613

VL - 2021

SP - 1

EP - 31

JO - Immunity

JF - Immunity

IS - 00

ER -

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

Abstract

Bibliographical note

Keywords

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