Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing

Sebastian Willenborg; David E Sanin; Alexander Jais; Xiaolei Ding; Thomas Ulas; Julian Nüchel; Milica Popović; Thomas MacVicar; Thomas Langer; Joachim L Schultze; Alexander Gerbaulet; Axel Roers; Edward J Pearce; Jens C Brüning; Aleksandra Trifunovic; Sabine A Eming

doi:10.1016/j.cmet.2021.10.004

Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing

Cell Metab. 2021 Dec 7;33(12):2398-2414.e9. doi: 10.1016/j.cmet.2021.10.004. Epub 2021 Oct 28.

Authors

Sebastian Willenborg¹, David E Sanin², Alexander Jais³, Xiaolei Ding¹, Thomas Ulas⁴, Julian Nüchel⁵, Milica Popović⁶, Thomas MacVicar⁷, Thomas Langer⁸, Joachim L Schultze⁴, Alexander Gerbaulet⁹, Axel Roers⁹, Edward J Pearce¹⁰, Jens C Brüning¹¹, Aleksandra Trifunovic¹², Sabine A Eming¹³

Affiliations

¹ Department of Dermatology, University of Cologne, 50937 Cologne, Germany.
² Department of Immunometabolism, Max Planck Institute of Epigenetics and Immunobiology, 79108 Freiburg im Breisgau, Germany.
³ Max Planck Institute for Metabolism Research, 50931 Cologne, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany.
⁴ Genomics & Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany; Platform for Single Cell Genomics and Epigenomics (PRECISE) at the German Center for Neurodegenerative Diseases and the University of Bonn, 53127 Bonn, Germany.
⁵ Institute for Biochemistry II, Center for Biochemistry, University of Cologne, 50931 Cologne, Germany.
⁶ Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
⁷ Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
⁸ Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
⁹ Institute for Immunology, Medical Faculty, TU Dresden, 01307 Dresden, Germany.
¹⁰ Department of Immunometabolism, Max Planck Institute of Epigenetics and Immunobiology, 79108 Freiburg im Breisgau, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg im Breisgau, Germany.
¹¹ Max Planck Institute for Metabolism Research, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
¹² Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
¹³ Department of Dermatology, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany; Institute of Zoology, Developmental Biology Unit, University of Cologne, 50674 Cologne, Germany. Electronic address: [email protected].

PMID: 34715039
DOI: 10.1016/j.cmet.2021.10.004

Abstract

Wound healing is a coordinated process that initially relies on pro-inflammatory macrophages, followed by a pro-resolution function of these cells. Changes in cellular metabolism likely dictate these distinct activities, but the nature of these changes has been unclear. Here, we profiled early- versus late-stage skin wound macrophages in mice at both the transcriptional and functional levels. We found that glycolytic metabolism in the early phase is not sufficient to ensure productive repair. Instead, by combining conditional disruption of the electron transport chain with deletion of mitochondrial aspartyl-tRNA synthetase, followed by single-cell sequencing analysis, we found that a subpopulation of early-stage wound macrophages are marked by mitochondrial ROS (mtROS) production and HIF1α stabilization, which ultimately drives a pro-angiogenic program essential for timely healing. In contrast, late-phase, pro-resolving wound macrophages are marked by IL-4Rα-mediated mitochondrial respiration and mitohormesis. Collectively, we identify changes in mitochondrial metabolism as a critical control mechanism for macrophage effector functions during wound healing.

Keywords: metabolism; mitochondria; mitochondrial repurposing; mitohormesis; monocyte/macrophage; tissue repair; type 2 immunity; wound healing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Macrophages* / metabolism
Mice
Mitochondria / metabolism
Wound Healing*