Center for Molecular Medicine Cologne

Eming, Sabine - C 06

Metabolic regulation of myeloid cells in tissue repair and regeneration

Introduction

Recent advances in immunometabolism uncovered metabolic pathways in myeloid cells as one promising approach to regulate immune cell function. The role of metabolic pathways controlling immune cell function in tissue regenerative responses is unknown. The Eming group is interested to understand cellular mechanisms of metabolic control within the injured tissue and how this metabolic communication network can be exploited for the treatment of pathological wound healing conditions in patients. Findings generated in the Eming group during the current funding period demonstrate that both metabolic pathways in immune cells and stromal cells control the outcome of a tissue response and that metabolic dysbalance in these cell types provides an explanation for the spectrum of pathological repair phenotypes.

Myeloid cells are an essential component of the body’s innate ability to restore tissue function after injury

Skin injury induces a highly dynamic cellular programme proceeding in sequential phases of antimicrobial defence, followed by tissue growth and differentiation. Cells of the myeloid cell lineage are an essential component of the body’s innate ability to restore tissue function after injury. Our previous work showed that to ensure optimal skin wound healing, macrophages need to initially adopt a pro-inflammatory and pro-angiogenic phenotype (characterized by a type-1 immune response), and later once immediate danger has passed to acquire a resolution phenotype (characterized by a type-2 immune response) to promote repair. Our aim is to further explore signalling pathways and transcriptional networks in macrophages that coordinate their functional plasticity during the sequential repair stages and to understand whether metabolic programmes impact these processes. Using a combination of gene-modified mouse models and transcriptome profiling, the Eming group could show that metabolic reprogramming in macrophages coordinates critical stage-specific repair processes during wound healing.

Figure 1

Perspectives

Our studies may inspire novel and exciting avenues to understand perturbed immune cell function and to develop therapeutic approaches for the treatment of chronic inflammation and pathological wound healing conditions in patients. The Eming group proposes to combine the metabolic knowledge gained in their pre-clinical skin injury model in mice with their long-standing clinical expertise in wound healing disorders in patients.

  • Sanin DE *, Ge Y , Marinkovic E, Kabat AM, Castoldi A, Caputa G, Grzes KM, Curtis JD, Willenborg S, Dichtl S, Dahl A, Pearce EL, Eming SA*, Gerbaulet A*, Roers A*, Murray PJ*, Pearce EJ* A common framework of monocyte-derived macrophage activation. Sci Immunol7(70):eabl7482, 2022* corresponding authors
  • Dichtl S, Sanin DE, Koss CK, Willenborg S, Petzold A, Tanzer MC, Dahl A, Kabat AM, Lindenthal L, Zeitler L, Satzinger S, Strasser A, Mann M, Roers A, Eming SA, El Kasmi KC, Pearce EJ, Murray PJ. Gene-selective transcription promotes the inhibition of tissue reparative macrophages by TNF. Life Sci Alliance. 13;5(4):e202101315, 2022
  • Willenborg S, Sanin DE, Jais A, Ding X, Ulas T, Nüchel J, Popović M, MacVicar T, Langer T, Schultze JL, Gerbaulet A, Roers A, Pearce EJ, Brüning JC, Trifunovic A, Eming SA. Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metab33:2398-2414, 2021
  • Eming, S.A., Murray, P.J., Pearce, E.J. Metabolic orchestration of the wound healing response. Cell Metab9:S1550-4131(21)00362-4, 2021
  • Ding, X., Willenborg, S., Bloch, W., Wickström, S.A., Wagle, P., Brodesser, S., Roers, A., Jais, A., Brüning, J.C., Hall, M.N., Rüegg, M.A., Eming, S.A. Epidermal mTORC2 controls lipid synthesis and filaggrin processing in epidermal barrier formation. J. Allergy Clin. Immunol. 145, 283-300, 2020
  • Kim, C.S.*, Ding, X.*, Allmeroth, K., Biggs, L.C., Kolenc, O.I., L'Hoest, N., Chacón-Martínez, C.A., Edlich-Muth, C., Giavalisco, P., Quinn, K.P., Denzel, M.S., Eming, S.A.#, Wickström, S.A.#. Glutamine Metabolism controls stem cell fate reversibility and long-term maintenance in the hair follicle. Cell Metab. 32:629-642.e8, 2020 (IF 21) * equal first authorship, # corresponding authors
  • Schiffmann, L.M., Werthenbach, J.P., Heintges-Kleinhofer, F., Seeger, J.M., Fritsch, M., Günther, S.D., Willenborg, S., Brodesser, S., Lucas, C., Jüngst, C., Albert, M.C., Schorn, F., Witt, A., Moraes, C.T., Bruns, C.J., Pasparakis, M., Krönke, M., Eming, S.A., Coutelle, O., Kashkar, H. Mitochondrial respiration controls neoangiogenesis during wound healing and tumor growth. Nat Commun.11:3653, 2020
  • Eming, S.A., Wynn, T.M., and Martin, P. (2017). Inflammation and metabolism in tissue regeneration and repair. Science 356, 1026-1030.
  • Knipper, J.A., Willenborg, S., Brinckmann, J., Bloch, W., Maaß, T., Wagener, R., Willenborg, S., Krieg, T., Sutherland, T., Migge, T., Richardson, R., Hammerschmidt, M., Allen, J.E., and Eming, S.A. (2015). IL-4Rα signaling in myeloid cells controls collagen fibril assembly in skin repair. Immunity 43, 803-816.
  • Eming, S.A., Martin, P., and Tomic-Canic, M. (2014). Wound Repair and Regeneration: Mechanisms, signaling, and translation. Sci. Transl. Med. 6, 265sr6.
  • Willenborg, S., Lucas, T., Geert van Loo, G., Knipper, J., Krieg, T., Haase., I., Brachvogel, B., Hammerschmidt, M., Nagy, A., Ferrara, N., Pasparakis, M., and Eming, S.A. (2012) CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood 120, 613-625.
  • Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Müller W, Roers A, Eming SA, (2010) Differential roles of macrophages in diverse phases of skin repair. J Immunol 184(7):3964-77
  • Dichtl S, Sanin DE, Koss CK, Willenborg S, Petzold A, Tanzer MC, Dahl A, Kabat AM, Lindenthal L, Zeitler L, Satzinger S, Strasser A, Mann M, Roers A, Eming SA, El Kasmi KC, Pearce EJ, and Murray PJ (2022). Gene-selective transcription promotes the inhibition of tissue reparative macrophages by TNF. Life Sci Alliance5. doi:10.26508/lsa.202101315.
  • Sanin DE, Ge Y, Marinkovic E, Kabat AM, Castoldi A, Caputa G, Grzes KM, Curtis JD, Thompson EA, Willenborg S, Dichtl S, Reinhardt S, Dahl A, Pearce EL, Eming SA, Gerbaulet A, Roers A, Murray PJ, and Pearce EJ (2022). A common framework of monocyte-derived macrophage activation. Sci Immunol7, eabl7482. doi:10.1126/sciimmunol.abl7482.
  • Wang J, Eming SA, and Ding X (2022). Role of mTOR Signaling Cascade in Epidermal Morphogenesis and Skin Barrier Formation. Biology (Basel)11. doi:10.3390/biology11060931.
  • Willenborg S, Roscito JG, Gerbaulet A, Roers A, Dahl A, Eming SA, and Reinhardt S (2022). Isolation of macrophages from mouse skin wounds for single-cell RNA sequencing. STAR Protoc 3, 101337. doi:10.1016/j.xpro.2022.101337.
  • Singh K, Maity P, Koroma AK, Basu A, Pandey RK, Vander Beken S, Haas P, Krug L, Hainzl A, Sindrilaru A, Pfeiffer C, Wlaschek M, Frank NY, Frank MH, Ganss C, Bánvölgyi A, Wikonkál N, Eming S, Pastar I, Tomic-Canic M, Kluth MA, Scharffetter-Kochanek K. Angiogenin Released from ABCB5+ Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis. J Invest Dermatol. 142(6):1725-1736.e10, 2022. 
  • Welcker D, Stein C, Feitosa NM, Armistead J, Zhang JL, Lutke S, Kleinridders A, Bruning JC, Eming SA, Sengle G, Niehoff A, Bloch W, and Hammerschmidt M (2021). Hemicentin-1 is an essential extracellular matrix component of the dermal-epidermal and myotendinous junctions. Sci Rep11, 17926. doi:10.1038/s41598-021-96824-4.
    • Willenborg S, Sanin DE, Jais A, Ding X, Ulas T, Nuchel J, Popovic M, MacVicar T, Langer T, Schultze JL, Gerbaulet A, Roers A, Pearce EJ, Bruning JC, Trifunovic A, and Eming SA (2021). Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metab33, 2398-2414 e2399. doi:10.1016/j.cmet.2021.10.004.
    • Ding X, Kakanj P, Leptin M, and Eming SA (2021). Regulation of the Wound Healing Response during Aging. J Invest Dermatol141, 1063-1070. doi:10.1016/j.jid.2020.11.014.
    • Eming SA, Murray PJ, and Pearce EJ (2021). Metabolic orchestration of the wound healing response. Cell Metab33, 1726-1743. doi:10.1016/j.cmet.2021.07.017.
    • Hadrian K, Willenborg S, Bock F, Cursiefen C, Eming SA, and Hos D (2021). Macrophage-Mediated Tissue Vascularization: Similarities and Differences Between Cornea and Skin. Front Immunol12, 667830. doi:10.3389/fimmu.2021.667830.
    • Ding X, Willenborg S, Bloch W, Wickstrom SA, Wagle P, Brodesser S, Roers A, Jais A, Bruning JC, Hall MN, Ruegg MA, and Eming SA (2020). Epidermal mammalian target of rapamycin complex 2 controls lipid synthesis and filaggrin processing in epidermal barrier formation. J Allergy Clin Immunol145, 283-300 e288. doi:10.1016/j.jaci.2019.07.033.
    • Kakanj P, Eming SA, Partridge L, and Leptin M (2020). Long-term in vivo imaging of Drosophila larvae. Nat Protoc15, 1158-1187. doi:10.1038/s41596-019-0282-z.
    • Kim CS, Ding XL, Allmeroth K, Biggs LC, Kolenc OI, L'Hoest N, Chacon-Martinez CA, Edlich-Muth C, Giavalisco P, Quinn KP, Denzel MS, Eming SA, and Wickstrom SA (2020). Glutamine Metabolism Controls Stem Cell Fate Reversibility and Long-Term Maintenance in the Hair Follicle. Cell Metabolism32, 629-+. doi:10.1016/j.cmet.2020.08.011.
    • Schiffmann LM, Werthenbach JP, Heintges-Kleinhofer F, Seeger JM, Fritsch M, Gunther SD, Willenborg S, Brodesser S, Lucas C, Jungst C, Albert MC, Schorn F, Witt A, Moraes CT, Bruns CJ, Pasparakis M, Kronke M, Eming SA, Coutelle O, and Kashkar H (2020). Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth. Nature Communications11. doi:Artn 3653 10.1038/S41467-020-17472-2.
    • Schönborn K, Willenborg S,  Schulz J N, Imhof T, Eming S A, Quondamatteo F, Brinckmann J,  Niehoff A, Paulsson M, Koch M, Eckes B, Krieg T. Role of collagen XII in skin homeostasis and repair. Matrix Biol 2020 Vol. 94 Pages 57-76, Accession Number: 32890632 DOI: 10.1016/j.matbio.2020.08.002.
    Prof. Dr. Sabine Eming CMMC Cologne
    Prof. Dr. Sabine Eming

    Clinic of Dermatology and Venereology

    CMMC - Vice Chair

    CMMC - PI - C 06

    +49 221 478 3196

    +49 221 478 5949

    Clinic of Dermatology and Venereology

    Kerpener Str. 62

    50937 Cologne

    http://www.eming.uni-koeln.de/Sabine_Eming_Research_Group_-_Uni_Koln/Sabine_Eming_-_Uni_Koln.html

    CMMC Profile Page

    Curriculum Vitae (CV)

    Publications - Sabine Eming

    Link to PubMed

    Awards & Appointments
    • 2022: Secretary-Treasurer and President-Elect, European Society for Dermatological Research
    • since 2020: Member DFG Fachkollegium Medicine
    • 2020: Member of the National Academy Leopoldina
    • 2020: Founding Board Member, International Society for Regenerative Biology
    • 2018: Board Member, European Society for Dermatological Research
    • 2017: Oscar-Gans-Award, Deutsche Dermatologische Gesellschaft
    • 2012 - 2015: President, Arbeitsgemeinschaft Dermatologische Forschung
    • 2013: Chair, Gordon Research Conference, Tissue Repair and Regeneration
    • 2013: Science Award, Berlin Foundation for Dermatology
    • 2009 - 2011: President, European Tissue Repair Society
    • 2007: Victor von Bruns Award, German Wound Healing Society
    • 2004: Award of NRW Universities for best patent application
    • 1996: La Roche-Posay Award for Biology