TY - JOUR
T1 - IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation
AU - Faas, Maria
AU - Ipseiz, Natacha
AU - Ackermann, Jochen
AU - Culemann, Stephan
AU - Grüneboom, Anika
AU - Schröder, Fenja
AU - Rothe, Tobias
AU - Scholtysek, Carina
AU - Eberhardt, Martin
AU - Böttcher, Martin
AU - Kirchner, Philipp
AU - Stoll, Cornelia
AU - Ekici, Arif
AU - Fuchs, Maximilian
AU - Kunz, Meik
AU - Weigmann, Benno
AU - Wirtz, Stefan
AU - Lang, Roland
AU - Hofmann, Joerg
AU - Vera, Julio
AU - Voehringer, David
AU - Michelucci, Alessandro
AU - Mougiakakos, Dimitrios
AU - Uderhardt, Stefan
AU - Schett, Georg
AU - Krönke, Gerhard
N1 - Funding Information:
We thank A. Klej, R. Weinkam, and R. Palmisano as well as the Optical Imaging Center Erlangen (OICE) for excellent technical assistance. M. Mroz and U. Appelt provided help during cell sorting. We want to additionally thank Yolanda Pires-Afonso from the Luxembourg Institute of Health (LIH) for help during isolation of macrophages from Irg1?/? mice. This work was supported by Deutsche Forschungsgemeinschaft (DFG; CRC1181-A03/A01/A02/Z2 to G.K. G.S. and D.V.; GK1660 to G.K.; and FG 2886 ?PANDORA? ? B01/A03 to G.K. and G.S.), the Emerging Field Initiative (EFI) of Friedrich-Alexander University Erlangen-N?rnberg (FAU) (EFI_Verbund_Med_05_MIRACLE to G.K.), Bundesministerium f?r Bildung und Forschung (BMBF) (MASCARA to G.K. and G.S. MelAutim (FKZ:01ZX1905A) to G.K. and J.V.-G.), and the European Union (Horizon 2020 ERC-2014-StG 640087 ? SOS and Horizon 2020 ERC-2020-CoG 101001866 to G.K. as well as Horizon 2020 ERC-2018-SyG nanoSCOPE and RTCure to G.S.). Volume imaging was performed on a Zeiss LSM 880 system, funded by DFG (German Research Foundation), project 261193037. M. Faas. N.I. J.A. S.C. and S.U. designed the study, performed experiments, interpreted results, and wrote the manuscript. A.G. F.S. J.H. C. Scholtysek, C. Stoll, and M.B. performed experiments, collected data, and interpreted results. B.W. S.W. D.V. R.L. and A.M. provided expertise, essential material, and input and wrote the manuscript. P.K. M.E. A.E. M. Fuchs. M.K. and J.V.-G. performed bioinformatics analysis and interpreted the data. D.M. and G.S. wrote the manuscript and provided valuable input. G.K. designed the study and experiments and wrote the manuscript. All authors read and commented on the manuscript. The authors declare no competing interests
Funding Information:
We thank A. Klej, R. Weinkam, and R. Palmisano as well as the Optical Imaging Center Erlangen (OICE) for excellent technical assistance. M. Mroz and U. Appelt provided help during cell sorting. We want to additionally thank Yolanda Pires-Afonso from the Luxembourg Institute of Health (LIH) for help during isolation of macrophages from Irg1 −/− mice. This work was supported by Deutsche Forschungsgemeinschaft (DFG; CRC1181-A03/A01/A02/Z2 to G.K., G.S., and D.V.; GK1660 to G.K.; and FG 2886 “PANDORA” – B01/A03 to G.K. and G.S.), the Emerging Field Initiative (EFI) of Friedrich-Alexander University Erlangen-Nürnberg (FAU) ( EFI_Verbund_Med_05_MIRACLE to G.K.), Bundesministerium für Bildung und Forschung (BMBF) ( MASCARA to G.K. and G.S., MelAutim ( FKZ:01ZX1905A ) to G.K. and J.V.-G.), and the European Union (Horizon 2020 ERC-2014-StG 640087 – SOS and Horizon 2020 ERC-2020-CoG 101001866 to G.K. as well as Horizon 2020 ERC-2018-SyG nanoSCOPE and RTCure to G.S.). Volume imaging was performed on a Zeiss LSM 880 system, funded by DFG (German Research Foundation), project 261193037 .
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/11/9
Y1 - 2021/11/9
N2 - Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.
AB - Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.
KW - alternatively activated macrophage
KW - GATA3
KW - interleukin-33
KW - itaconate
KW - mitochondrial rewiring
KW - resolution of inlammation
KW - UCP2
KW - uncoupling
UR - http://www.scopus.com/inward/record.url?scp=85118539315&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/34644537
U2 - 10.1016/j.immuni.2021.09.010
DO - 10.1016/j.immuni.2021.09.010
M3 - Article
C2 - 34644537
AN - SCOPUS:85118539315
SN - 1074-7613
VL - 54
SP - 2531-2546.e5
JO - Immunity
JF - Immunity
IS - 11
ER -