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

被引：182

作者：

Friscic, Jasna ^{[1
,2
,3
]}

Bottcher, Martin ^{[2
,3
,4
]}

Reinwald, Christiane ^{[1
,2
,3
]}

Bruns, Heiko ^{[2
,3
,4
]}

Wirth, Benjamin ^{[1
,2
,3
]}

Popp, Samantha-Josefine ^{[2
,3
,4
]}

Walker, Kellie Irene ^{[5
]}

Ackermann, Jochen A. ^{[1
,2
,3
]}

Chen, Xi ^{[1
,2
,3
]}

Turner, Jason ^{[6
]}

Zhu, Honglin ^{[1
,2
,3
,7
]}

Seyler, Lisa ^{[2
,8
]}

Euler, Maximilien ^{[1
,2
,3
]}

Kirchner, Philipp ^{[2
,9
]}

Krueger, Rene ^{[2
,9
,10
]}

Ekici, Arif B. ^{[2
,9
]}

Major, Triin ^{[6
]}

Aust, Oliver ^{[1
,2
,3
]}

Weidner, Daniela ^{[1
,2
,3
]}

Fischer, Anita ^{[11
,12
]}

Andes, Fabian T. ^{[1
,2
,3
]}

Stanojevic, Zeljka ^{[13
]}

Trajkovic, Vladimir ^{[14
]}

Herrmann, Martin ^{[1
,2
,3
]}

Korb-Pap, Adelheid ^{[15
]}

Wank, Isabel ^{[16
]}

Hess, Andreas ^{[16
]}

Winter, Johnathan ^{[17
]}

Wixler, Viktor ^{[18
]}

Distler, Jorg ^{[1
,2
,3
]}

Steiner, Guenter ^{[11
,12
]}

Kiener, Hans P. ^{[11
]}

Frey, Benjamin ^{[19
]}

Kling, Lasse ^{[20
]}

Raza, Karim ^{[6
,21
]}

Frey, Silke ^{[1
,2
,3
]}

Kleyer, Arnd ^{[1
,2
,3
]}

Baeuerle, Tobias ^{[2
,8
]}

Hughes, Timothy R. ^{[17
]}

Grueneboom, Anika ^{[1
,2
,3
]}

Steffen, Ulrike ^{[1
,2
,3
]}

Kroenke, Gerhard ^{[1
,2
,3
]}

Croft, Adam P. ^{[6
]}

Filer, Andrew ^{[6
]}

Koehl, Joerg ^{[22
,23
,24
]}

Klein, Kerstin ^{[5
]}

Buckley, Christopher D. ^{[6
,25
]}

Schett, Georg ^{[1
,2
,3
]}

Mougiakakos, Dimitrios ^{[2
,3
,4
]}

Hoffmann, Markus H. ^{[1
,2
,3
]}

机构：

[1] Friedrich Alexander Univ Erlangen Nurnberg FAU, Dept Internal Med Rheumatol & Immunol 3, D-91054 Erlangen, Germany

[2] Univ Klinikum Erlangen, D-91054 Erlangen, Germany

[3] Friedrich Alexander Univ Erlangen Nurnberg FAU, Deutsch Zentrum Immuntherapie, D-91054 Erlangen, Germany

[4] Friedrich Alexander Univ Erlangen Nurnberg, Dept Med Hematol & Oncol 5, D-91054 Erlangen, Germany

[5] Univ Zurich, Univ Hosp Zurich, Ctr Expt Rheumatol, Dept Rheumatol, CH-8091 Zurich, Switzerland

[6] Univ Birmingham, Univ Hosp Birmingham NHS Fdn Trust, NIHR Birmingham Biomed Res Ctr, Inst Inflammat & Ageing, Birmingham B15 2TT, W Midlands, England

[7] Cent South Univ, Xiangya Hosp, Dept Rheumatol, Changsha 410008, Hunan, Peoples R China

[8] Friedrich Alexander Univ Erlangen Nurnberg FAU, Inst Radiol, D-91054 Erlangen, Germany

[9] Friedrich Alexander Univ Erlangen Nurnberg FAU, Inst Human Genet, D-91054 Erlangen, Germany

[10] Friedrich Alexander Univ Erlangen Nurnberg FAU, Dept Nephrol & Hypertens, D-91054 Erlangen, Germany

[11] Med Univ Vienna, Div Rheumatol, Dept Med 3, A-1090 Vienna, Austria

[12] Ludwig Boltzmann Inst Arthrit & Rehabil, A-1090 Vienna, Austria

[13] Univ Belgrade, Fac Med, Inst Med & Clin Biochem, Belgrade 11000, Serbia

[14] Univ Belgrade, Fac Med, Inst Microbiol & Immunol, Belgrade 11000, Serbia

[15] Univ Hosp Muenster, Inst Musculoskeletal Med, Albert Schweitzer Campus 1,D3, D-48149 Munster, Germany

[16] Friedrich Alexander Univ Erlangen Nurnberg FAU, Inst Expt & Clin Pharmacol & Toxicol, D-91054 Erlangen, Germany

[17] Cardiff Univ, Sch Med, Div Infect & Immun, Cardiff CF10 3AT, Wales

[18] Westfaelische Wilhelms Univ Muenster, Ctr Mol Biol Inflammat ZMBE, Inst Mol Virol IMV, D-48149 Munster, Germany

[19] Friedrich Alexander Univ Erlangen Nurnberg FAU, Dept Radiat Oncol, D-91054 Erlangen, Germany

[20] Innovat Inst Nanotechnol & Korrelat Mikroskopie, D-91301 Forchheim, Germany

[21] City Hosp, Dept Rheumatol, Birmingham B18 7QH, W Midlands, England

[22] Univ Lubeck, Inst Syst Inflammat Res, D-23562 Lubeck, Germany

[23] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA

[24] Univ Cincinnati, Coll Med, Cincinnati, OH 45229 USA

[25] Univ Oxford, Kennedy Inst Rheumatol, Oxford OX3 7FY, England

来源：

IMMUNITY | 2021年 / 54卷 / 05期

基金：

英国医学研究理事会; 芬兰科学院;

关键词：

NLRP3; INFLAMMASOME; RHEUMATOID-ARTHRITIS; CELL HOMEOSTASIS; READ ALIGNMENT; RECEPTOR; IL-1-BETA; MICE; ACTIVATION; EXPRESSION; C3A;

D O I：

10.1016/j.immuni.2021.03.003

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined themolecular 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 1 alpha-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.

引用

页码：1002 / +

页数：30

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